Inhibitors of protein tyrosine kinase activity

ABSTRACT

This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling and HGF receptor signaling. More particularly, the invention relates to compounds, compositions and methods for the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/968,673, filed Aug. 29, 2007. The entire teachings of theabove-referenced application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds that inhibit protein tyrosine kinaseactivity. In particular the invention relates to compounds that inhibitthe protein tyrosine kinase activity of growth factor receptors,resulting in the inhibition of receptor signaling, for example, theinhibition of VEGF receptor signaling and HGF receptor signaling. Moreparticularly, the invention relates to compounds, compositions andmethods for the inhibition of VEGF receptor signaling and HGF receptorsignaling.

2. Summary of the Related Art

Tyrosine kinases may be classified as growth factor receptor (e.g. EGFR,PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases.The receptor type tyrosine kinases make up about 20 differentsubfamilies. The non-receptor type tyrosine kinases make up numeroussubfamilies. These tyrosine kinases have diverse biological activity.Receptor tyrosine kinases are large enzymes that span the cell membraneand possess an extracellular binding domain for growth factors, atransmembrane domain, and an intracellular portion that functions as akinase to phosphorylate a specific tyrosine residue in proteins andhence to influence cell proliferation. Aberrant or inappropriate proteinkinase activity can contribute to the rise of disease states associatedwith such aberrant kinase activity.

Angiogenesis is an important component of certain normal physiologicalprocesses such as embryogenesis and wound healing, but aberrantangiogenesis contributes to some pathological disorders and inparticular to tumor growth. VEGF-A (vascular endothelial growth factorA) is a key factor promoting neovascularization (angiogenesis) oftumors. VEGF induces endothelial cell proliferation and migration bysignaling through two high affinity receptors, the fms-like tyrosinekinase receptor, Flt-1, and the kinase insert domain-containingreceptor, KDR. These signaling responses are critically dependent uponreceptor dimerization and activation of intrinsic receptor tyrosinekinase (RTK) activity. The binding of VEGF as a disulfide-linkedhomodimer stimulates receptor dimerization and activation of the RTKdomain. The kinase activity autophosphorylates cytoplasmic receptortyrosine residues, which then serve as binding sites for moleculesinvolved in the propagation of a signaling cascade. Although multiplepathways are likely to be elucidated for both receptors, KDR signalingis most extensively studied, with a mitogenic response suggested toinvolve ERK-1 and ERK-2 mitogen-activated protein kinases.

Disruption of VEGF receptor signaling is a highly attractive therapeutictarget in cancer, as angiogenesis is a prerequisite for all solid tumorgrowth, and that the mature endothelium remains relatively quiescent(with the exception of the female reproductive system and woundhealing). A number of experimental approaches to inhibiting VEGFsignaling have been examined, including use of neutralizing antibodies,receptor antagonists, soluble receptors, antisense constructs anddominant-negative strategies.

Despite the attractiveness of anti-angiogenic therapy by VEGF inhibitionalone, several issues may limit this approach. VEGF expression levelscan themselves be elevated by numerous diverse stimuli and perhaps mostimportantly, the hypoxic state of tumors resulting from VEGFrinhibition, can lead to the induction of factors that themselves promotetumor invasion and metastasis thus, potentially undermining the impactof VEGF inhibitors as cancer therapeutics.

The HGF (hepatocyte growth factor) and the HGF receptor, c-met, areimplicated in the ability of tumor cells to undermine the activity ofVEGF inhibition. HGF derived from either stromal fibroblasts surroundingtumor cells or expressed from the tumor itself has been suggested toplay a critical role in tumor angiogenesis, invasion and metastasis. Forexample, invasive growth of certain cancer cells is drastically enhancedby tumor-stromal interactions involving the HGF/c-Met (HGF receptor)pathway. HGF, which was originally identified as a potent mitogen forhepatocytes is primarily secreted from stromal cells, and the secretedHGF can promote motility and invasion of various cancer cells thatexpress c-Met in a paracrine manner. Binding of HGF to c-Met leads toreceptor phosphorylation and activation of Ras/mitogen-activated proteinkinase (MAPK) signaling pathway, thereby enhancing malignant behaviorsof cancer cells. Moreover, stimulation of the HGF/c-met pathway itselfcan lead to the induction of VEGF expression, itself contributingdirectly to angiogenic activity.

Thus, anti-tumor anti-angiogenic strategies or approaches that targetboth VEGF/VEGFr signaling and HGF/c-met signaling may circumvent theability of tumor cells to overcome VEGF inhibition alone and mayrepresent improved cancer therapeutics.

Tyrosine kinases also contribute to the pathology of opthalmologicaldiseases, disorders and conditions, such as age-related maculardegeneration (AMD) and diabetic retinopathy (DR). Blindness from suchdiseases has been linked to anomalies in retinal neovascularization. Theformation of new blood vessels is regulated by growth factors such asVEGF and HGF that activate receptor tyrosine kinases resulting in theinitiation of signaling pathways leading to plasma leakage into themacula, causing vision loss. Recently, the Ax1 receptor tyrosine kinasehas been implicated in the process of angiogenesis, by regulating cellsurvival, motility and invasions. These kinases are thus attractivetargets for the treatment of eye diseases involving neovascularization.

Thus, there is a need to develop a strategy for controllingneovascularization of the eye and to develop a strategy for thetreatment of ocular diseases.

Here we describe small molecules that are potent inhibitors of proteintyrosine kinase activity, such as that of, for example, both the VEGFreceptor KDR and the HGF receptor c-met.

BRIEF SUMMARY OF THE INVENTION

The present invention provides new compounds and methods for treating adisease responsive to inhibition of kinase activity, for example adisease responsive to inhibition of protein tyrosine kinse activity, forexample a disease responsive to inhibition of protein tyrosine kinaseactivity of growth factor receptors. The present invention also providesnew compounds and methods for treating a disease responsive toinhibition of receptor type tyrosine kinase signaling, for example, adisease responsive to inhibition of VEGF receptor signaling and HGFreceptor signaling. In one embodiment the disease is a cellproliferative disease. The compounds of the invention are inhibitors ofprotein tyrosine kinase activity. In one embodiment, the compounds ofthe invention are dual function inhibitors, capable of inhibiting bothVEGF and HGF receptor signaling. Accordingly, the invention provides newinhibitors of protein tyrosine kinase receptor signaling, such as forexample, VEGF receptor signaling and HGF receptor signaling, includingthe VEGF receptor KDR and the HGF receptor c-met.

In a first aspect, the invention provides compounds of Formula (I) thatare useful as kinase inhibitors:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, and racemic and scalemic mixtures,diastereomers and enantiomers thereof, wherein D, M, Z, Ar and G are asdefined herein. Because compounds of the present invention are useful askinase inhibitors they are, therefore, useful research tools for thestudy of the role of kinases in both normal and disease states. In oneembodiment, the invention provides compounds that are useful asinhibitors of VEGF receptor signaling and HGF receptor signaling and,therefore, are useful research tools for the study of the role of VEGFand HGF in both normal and disease states.

Reference to “a compound of the formula (I)”, (or equivalently, “acompound according to the first aspect”, or “a compound of the presentinvention”, and the like), herein is understood to include reference toN-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, and racemic and scalemic mixtures,diastereomers, enantiomers and tautomers thereof, unless otherwiseindicated.

In a second aspect, the invention provides compositions comprising acompound according to the present invention, or an N-oxide, hydrate,solvate, pharmaceutically acceptable salt, prodrug or complex thereof,or a racemic or scalemic mixture, diastereomers or enantiomer thereof,and a pharmaceutically acceptable carrier, excipient or diluent. Forexample, the invention provides compositions comprising a compound thatis an inhibitor of VEGF receptor signaling and HGF receptor signaling,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, excipient, or diluent.

In a third aspect, the invention provides a method of inhibiting kinaseactivity, for example protein tyrosine kinase, for example tyrosinekinase activity of a growth factor receptor, the method comprisingcontacting the kinase with a compound according to the presentinvention, or with a composition according to the present invention. Inanother embodiment of this aspect, the invention provides a method ofinhibiting receptor type tyrosine kinase signaling, for exampleinhibiting VEGF receptor signaling and HGF receptor signaling.Inhibition can be in a cell or a multicellular organism. If in a cell,the method according to this aspect of the invention comprisescontacting the cell with a compound according to the present invention,or with a composition according to the present invention. If in amulticellular organism, the method according to this aspect of theinvention comprises administering to the organism a compound accordingto the present invention, or a composition according to the presentinvention. In one embodiment the organism is a mammal, for example aprimate, for example a human.

In a fourth aspect, the invention provides a method of inhibitingangiogenesis, the method comprising administering to a patient in needthereof a therapeutically effective amount of a compound according tothe present invention, or a therapeutically effective amount of acomposition according to the present invention. In one embodiment ofthis aspect, the angiogenesis to be inhibited is involved in tumorgrowth. In another embodiment the angiogenesis to be inhibited isretinal angiogenesis. In another embodiment of this aspect, the patientis a mammal, for example a primate, for example a human.

In a fifth aspect, the invention provides a method of treating a diseaseresponsive to inhibition of kinase activity, for example a diseaseresponsive to inhibition of protein tyrosine kinase activity, forexample a disease responsive to inhibition of protein tyrosine kinaseactivity of growth factor receptors. In another embodiment of thisaspect, the invention provides a method of treating a disease responsiveto inhibition of receptor type tyrosine kinase signaling, for example adisease responsive to inhibition of VEGF receptor signaling and HGFreceptor signaling, the method comprising administering to an organismin need thereof a therapeutically effective amount of a compoundaccording to the present invention, or a composition according to thepresent invention. In one embodiment of this aspect, the organism is amammal, for example a primate, for example a human.

In a sixth aspect, the invention provides a method of treating a cellproliferative disease, the method comprising administering to a patientin need thereof a therapeutically effective amount of a compoundaccording to the present invention, or a therapeutically effectiveamount of a composition according to the present invention. In certainembodiments of this aspect, the cell proliferative disease is cancer. Inan embodiment, the patient is a mammal, for example a primate, forexample a human.

In a seventh aspect, the invention provides a method of treating anophthalmic disease, disorder or condition, the method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to the present invention, or atherapeutically effective amount of a composition according to thepresent invention. In one embodiment of this aspect, the disease iscaused by choroidal angiogenesis. In some embodiments of this aspect,the patient is a mammal, for example a primate, for example a human.

In an eighth aspect, the invention provides for the use of a compoundaccording to the present invention for the manufacture of a medicamentto inhibit kinase activity, for example to inhibit protein tyrosinekinase activity, for example to inhibit protein tyrosine kinase activityof growth factor receptors. In another embodiment of this aspect, theinvention provides for the use of a compound according to the presentinvention for the manufacture of a medicament to inhibit receptor typetyrosine kinase signaling, for example to inhibit VEGF receptorsignaling and HGF receptor signaling. In certain embodiments of thisaspect, the invention provides for the use of a compound according tothe present invention for the manufacture of a medicament to treat adisease responsive to inhibition of kinase activity. In certainembodiments of this aspect, the disease is responsive to inhibition ofprotein tyrosine kinase activity, for example inhibition of proteintyrosine kinase activity of growth factor receptors. In anotherembodiment of this aspect, the disease is responsive to inhibition ofreceptor type tyrosine kinase signaling, for example VEGF receptorsignaling and HGF receptor signaling. In another embodiment embodiment,the disease is a cell proliferative disease, for example cancer. Inanother embodiment of this aspect, the disease is an ophthalmic disease,disorder or condition. In one embodiment of this aspect, the ophthalmicdisease, disorder or condition is caused by choroidal angiogenesis. Inanother embodiment of this aspect, the disease is age-related maculardegeneration, diabetic retinopathy or retinal edema.

In a nineth aspect, the invention provides for the use of a compoundaccording to the present invention, or a composition thereof, to inhibitkinase activity, for example to inhibit receptor type tyrosine kinaseactivity, for example to inhibit protein tyrosine kinase activity ofgrowth fractor receptors. In another embodiment of this aspect, theinvention provides for the use of a compound according to the presentinvention, or a composition thereof, to inhibit receptor type tyrosinekinase signaling, for example to inhibit VEGF receptor signaling and HGFreceptor signaling.

In a tenth aspect, the invention provides for the use of a compoundaccording to the present invention, or a composition thereof, to treat adisease responsive to inhibition of kinase activity, for example adisease responsive to inhibition of protein tyrosine kinase activity,for example a disease responsive to inhibition or protein tyrosinekinase activity of growth factor receptors. In another embodiment ofthis aspect, the invention provides for the use of a compound accordingto the present invention, or a composition thereof, to treat a diseaseresponsive to inhibition of receptor type tyrosine kinase signaling, forexample a disease responsive to inhibition of VEGF receptor signalingand HGF receptor signaling. In an embodiment of this aspect, the diseaseis a cell proliferative disease, for example cancer. In anotherembodiment of this aspect, the disease is an ophthalmic disease,disorder or condition. In another embodiment of this aspect, theophthalmic disease, disorder or condition is caused by choroidalangiogenesis.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds and methods for inhibiting kinaseactivity, for example protein tyrosine kinase activity, for examplereceptor protein kinase activity, for example the VEGF receptor KDR andthe HGF receptor c-met. The invention also provides compositions andmethods for inhibiting angiogenesis, treating a disease responsive toinhibition of kinase activity, treating cell proliferative diseases andconditions and treating ophthalmic diseases, disorders and conditions.The patent and scientific literature referred to herein reflectsknowledge that is available to those with skill in the art. The issuedpatents, published patent applications, and references that are citedherein are hereby incorporated by reference to the same extent as ifeach was specifically and individually indicated to be incorporated byreference. In the case of inconsistencies, the present disclosure willprevail.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety isA-B—.

For simplicity, reference to a “C_(n)-C_(m)” heterocyclyl or“C_(n)-C_(m)” heteroaryl means a heterocyclyl or heteroaryl having from“n” to “m” annular atoms, where “n” and “m” are integers. Thus, forexample, a C₅-C₆-heterocyclyl is a 5- or 6-membered ring having at leastone heteroatom, and includes pyrrolidinyl (C₅) and piperazinyl andpiperidinyl (C₆); C₆-heteroaryl includes, for example, pyridyl andpyrimidyl.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃ hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” is intended to mean a straight chain or branchedaliphatic group having from 1 to 12 carbon atoms, alternatively 1-8carbon atoms, and alternatively 1-6 carbon atoms. In some embodiments,the alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8carbon atoms and alternatively 2-6 carbon atoms. Examples of alkylgroups include, without limitation, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. A“C₀” alkyl (as in “C₀-C₃alkyl”) is a covalent bond.

The term “alkenyl” is intended to mean an unsaturated straight chain orbranched aliphatic group with one or more carbon-carbon double bonds,having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, andalternatively 2-6 carbon atoms. Examples alkenyl groups include, withoutlimitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” is intended to mean an unsaturated straight chain orbranched aliphatic group with one or more carbon-carbon triple bonds,having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, andalternatively 2-6 carbon atoms. Examples of alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The terms “alkylene,” “alkenylene,” or “alkynylene” as used herein areintended to mean an alkyl, alkenyl, or alkynyl group, respectively, asdefined hereinabove, that is positioned between and serves to connecttwo other chemical groups. Examples of alkylene groups include, withoutlimitation, methylene, ethylene, propylene, and butylene. Examples ofalkenylene groups include, without limitation, ethenylene, propenylene,and butenylene. Examples of alkynylene groups include, withoutlimitation, ethynylene, propynylene, and butynylene.

The term “carbocycle” as employed herein is intended to mean acycloalkyl or aryl moiety.

The term “cycloalkyl” is intended to mean a saturated, partiallyunsaturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbongroup having about 3 to 15 carbons, alternatively having 3 to 12carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, andalternatively 5 or 6 carbons. In certain alternative embodiments, thecycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group.Examples of cycloalkyl groups include, without limitation,cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone,cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

The term “heteroalkyl” is intended to mean a saturated, partiallyunsaturated or unsaturated, straight chain or branched aliphatic group,wherein one or more carbon atoms in the group are independently replacedby a heteroatom selected from the group consisting of O, S, and N.

The term “aryl” is intended to mean a mono-, bi-, tri- or polycyclicaromatic moiety, comprising one to three aromatic rings. In certainembodiments the aryl is a C₆-C₁₄aromatic moiety, alternatively the arylgroup is a C₆-C₁₀aryl group, alternatively a C₆ aryl group. Examples ofaryl groups include, without limitation, phenyl, naphthyl, anthracenyl,and fluorenyl.

The terms “aralkyl” or “arylalkyl” are intended to mean a groupcomprising an aryl group covalently linked to an alkyl group. If anaralkyl group is described as “optionally substituted”, it is intendedthat either or both of the aryl and alkyl moieties may independently beoptionally substituted or unsubstituted. In some embodiments, thearalkyl group is (C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation,benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as“arylalkyl” this term, and terms related thereto, is intended toindicate the order of groups in a compound as “aryl-alkyl”. Similarly,“alkyl-aryl” is intended to indicate the order of the groups in acompound as “alkyl-aryl”.

The terms “heterocyclyl”, “heterocyclic” or “heterocycle” are intendedto mean a group which is a mono-, bi-, or polycyclic structure havingfrom about 3 to about 14 atoms, wherein one or more atoms areindependently selected from the group consisting of N, O, and S. Thering structure may be saturated, unsaturated or partially unsaturated.In certain embodiments, the heterocyclic group is non-aromatic, in whichcase the group is also known as a heterocycloalkyl. In a bicyclic orpolycyclic structure, one or more rings may be aromatic; for example,one ring of a bicyclic heterocycle or one or two rings of a tricyclicheterocycle may be aromatic, as in indan and 9,10-dihydro anthracene.Examples of heterocyclic groups include, without limitation, epoxy,aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certainembodiments, the heterocyclic group is fused to an aryl, heteroaryl, orcycloalkyl group. Examples of such fused heterocycles include, withoutlimitation, tetrahydroquinoline and dihydrobenzofuran. Specificallyexcluded from the scope of this term are compounds where an annular O orS atom is adjacent to another O or S atom.

In certain embodiments, the heterocyclic group is a heteroaryl group. Asused herein, the term “heteroaryl” is intended to mean a mono-, bi-,tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6,9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclicarray; and having, in addition to carbon atoms, between one or moreheteroatoms independently selected from the group consisting of N, O,and S. For example, a heteroaryl group include, without limitation,pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl,benzofuranyl and indolinyl. Other examples of heteroaryl groups include,without limitation, thienyl, benzothienyl, furyl, benzofuryl,dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl,oxazolyl, thiazolyl, and isoxazolyl.

The terms “arylene,” “heteroarylene,” or “heterocyclylene” are intendedto mean an aryl, heteroaryl, or heterocyclyl group, respectively, asdefined hereinabove, that is positioned between and serves to connecttwo other chemical groups.

Examples of heterocyclyls and heteroaryls include, but are not limitedto, azepinyl, azetidinyl, acridinyl, azocinyl, benzidolyl,benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuryl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,benzothienyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, benzoxazolyl, benzoxadiazolyl,benzopyranyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, 1,3-dioxolane,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (such asfuor[2,3-c]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-b]pyridinyl),furyl, furazanyl, hexahydrodiazepinyl, imidazolidinyl, imidazolinyl,imidazolyl, indazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,isoxazolinyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, oxetanyl, 2-oxoazepinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolopyridyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydro-1,1-dioxothienyl, tetrahydrofuranyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl,tetrazolyl, thiazolidinyl, 6H-1,2,5-thiadiazinyl, thiadiazolyl (e.g.,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl), thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholuiyl sulfone, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, triazinylazepinyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), and xanthenyl.

The term “azolyl” as employed herein is intended to mean a five-memberedsaturated or unsaturated heterocyclic group containing two or morehetero-atoms, as ring atoms, selected from the group consisting ofnitrogen, sulfur and oxygen, wherein at least one of the hetero-atoms isa nitrogen atom. Examples of azolyl groups include, but are not limitedto, optionally substituted imidazolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.

As employed herein, and unless stated otherwise, when a moiety (e.g.,alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) isdescribed as “optionally substituted” it is meant that the groupoptionally has from one to four, alternatively from one to three,alternatively one or two, independently selected non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino,alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl,alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido,aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.

Examples of substituents, which are themselves not further substituted(unless expressly stated otherwise) are:

-   -   (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,        guanidino,    -   (b) C₁-C₅alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C₈alkyl, C₁-C₈alkenyl, C₁-C₈alkoxy,        C₁-C₈alkyamino, C₁-C₈alkoxycarbonyl, aryloxycarbonyl, C₂-C₈acyl,        C₂-C₈acylamino, C₁-C₈alkylthio, arylalkylthio, arylthio,        C₁-C₈alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl,        C₁-C₈alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl,        C₀-C₆N-alkyl carbamoyl, C₂-C₁₅N,N-dialkylcarbamoyl, C₃-C₇        cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to        a cycloalkyl or heterocycle or another aryl ring,        C₃-C₇heterocycle, C₅-C₁₅heteroaryl or any of these rings fused        or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein        each of the foregoing is further optionally substituted with one        more moieties listed in (a), above; and    -   (c) —(CR³²R³³)_(s)—NR³⁰R³¹,        -   wherein s is from 0 (in which case the nitrogen is directly            bonded to the moiety that is substituted) to 6,        -   R³² and R³³ are each independently hydrogen, halo, hydroxyl            or C₁-C₄alkyl, and R³⁰ and R³¹ are each independently            hydrogen, cyano, oxo, hydroxyl, C₁-C₈alkyl,            C₁-C₈heteroalkyl, C₁-C₈alkenyl, carboxamido,            C₁-C₃alkyl-carboxamido, carboxamido-C₁-C₃alkyl, amidino,            C₂-C₈hydroxyalkyl, C₁-C₃alkylaryl, aryl-C₁-C₃alkyl,            C₁-C₃alkylheteroaryl, heteroaryl-C₁-C₃alkyl,            C₁-C₃alkylheterocyclyl, heterocyclyl-C₁-C₃alkyl            C₁-C₃alkylcycloalkyl, cycloalkyl-C₁-C₃alkyl, C₂-C₈alkoxy,            C₂-C₈alkoxy-C₁-C₄alkyl, C₁-C₈alkoxycarbonyl,            aryloxycarbonyl, aryl-C₁-C₃alkoxycarbonyl,            heteroaryloxycarbonyl, heteroaryl-C₁-C₃alkoxycarbonyl,            C₁-C₈acyl, C₀-C₈alkyl-carbonyl, aryl-C₀-C₈alkyl-carbonyl,            heteroaryl-C₀-C₈alkyl-carbonyl,            cycloalkyl-C₀-C₈alkyl-carbonyl, C₀-C₈alkyl-NH-carbonyl,            aryl-C₀-C₈alkyl-NH-carbonyl,            heteroaryl-C₀-C₈alkyl-NH-carbonyl,            cycloalkyl-C₀-C₈alkyl-NH-carbonyl, C₀-C₈alkyl-O-carbonyl,            aryl-C₀-C₈alkyl-O-carbonyl,            heteroaryl-C₀-C₈alkyl-O-carbonyl,            cycloalkyl-C₀-C₈alkyl-O-carbonyl, C₁-C₈alkylsulfonyl,            arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl,            heteroarylsulfonyl, C₁-C₈alkyl-NH-sulfonyl,            arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl,            heteroarylalkyl-NH-sulfonyl, heteroaryl-NH-sulfonyl aroyl,            aryl, cycloalkyl, heterocyclyl, heteroaryl,            aryl-C₁-C₃alkyl-, cycloalkyl-C₁-C₃alkyl-,            heterocyclyl-C₁-C₃alkyl-, heteroaryl-C₁-C₃alkyl-, or            protecting group, wherein each of the foregoing is further            optionally substituted with one more moieties listed in (a),            above; or        -   R³⁰ and R³¹ taken together with the N to which they are            attached form a heterocyclyl or heteroaryl, each of which is            optionally substituted with from 1 to 3 substituents            selected from the group consisting of (a) above, a            protecting group, and (X³⁰—Y³¹—), wherein said heterocyclyl            may also be bridged (forming a bicyclic moiety with a            methylene, ethylene or propylene bridge); wherein        -   X³⁰ is selected from the group consisting of C₁-C₈alkyl,            C₂-C₈alkenyl-, C₂-C₈alkynyl-,            —C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃alkyl,            C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl,            C₀-C₃alkyl-O—C₀-C₃alkyl-, HO—C₀-C₃alkyl-,            C₀-C₄alkyl-N(R³⁰)—C₀-C₃alkyl-, N(R³⁰)(R³¹)—C₀-C₃alkyl-,            N(R³⁰)(R³¹)—C₀-C₃alkenyl-, N(R³⁰)(R³¹)—C₀-C₃alkynyl-,            (N(R³⁰)(R³¹))₂—C═N—, C₀-C₃alkyl-S(O)₀₋₂—C₀-C₃alkyl-,            CF₃—C₀-C₃alkyl-, C₁-C₈heteroalkyl, aryl, cycloalkyl,            heterocyclyl, heteroaryl, aryl-C₁-C₃alkyl-,            cycloalkyl-C₁-C₃alkyl-, heterocyclyl-C₁-C₃alkyl-,            heteroaryl-C₁-C₃alkyl-,            N(R³⁰)(R³¹)-heterocyclyl-C₁-C₃alkyl-, wherein the aryl,            cycloalkyl, heteroaryl and heterocycyl are optionally            substituted with from 1 to 3 substituents from (a); and        -   Y³¹ is selected from the group consisting of a direct bond,            —O—, —N(R³⁰)—, —C(O)—, —O—C(O)—, —C(O)—O—, —N(R³⁰)—C(O)—,            —C(O)—N(R³⁰)—, —N(R³⁰)—C(S)—, —C(S)—N(R³⁰)—,            —N(R³⁰)—C(O)—N(R³¹)—, —N(R³⁰)—C(NR³⁰)—N(R³¹)—,            —N(R³⁰)—C(NR³¹)—, —C(NR³¹)—N(R³⁰)—, —N(R³⁰)—C(S)—N(R³¹)—,            —N(R³⁰)—C(O)—O—, —O—C(O)—N(R³¹)—, —N(R³⁰)—C(S)—O—,            —O—C(S)—N(R³¹)—, —S(O)₀₋₂—, —SO₂N(R³¹)—, —N(R³¹)—SO₂— and            —N(R³⁰)—SO₂N(R³¹)—.

A moiety that is substituted is one in which one or more (for exampleone to four, alternatively from one to three and alternatively one ortwo), hydrogens have been independently replaced with another chemicalsubstituent. As a non-limiting example, substituted phenyls include2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl,2-fluoro-3-propylphenyl. As another non-limiting example, substitutedn-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl.Included within this definition are methylenes (—CH₂—) substituted withoxygen to form carbonyl —CO—.

When there are two optional substituents bonded to adjacent atoms of aring structure, such as for example a phenyl, thiophenyl, or pyridinyl,the substituents, together with the atoms to which they are bonded,optionally form a 5- or 6-membered cycloalkyl or heterocycle having 1,2, or 3 annular heteroatoms.

In certain embodiments, a hydrocarbyl, heteroalkyl, heterocyclic and/oraryl group is unsubstituted.

In other embodiments, a hydrocarbyl, heteroalkyl, heterocyclic and/oraryl group is substituted with from 1 to 3 independently selectedsubstituents.

Examples of substituents on alkyl groups include, but are not limitedto, hydroxyl, halogen (e.g., a single halogen substituent or multiplehalo substituents; in the latter case, groups such as CF₃ or an alkylgroup bearing Cl₃), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, heterocycle, aryl, —OR^(a), —SR^(a), —S(═O)R^(e),—S(═O)₂R^(e), —P(═O)₂R^(e), —S(═O)₂OR^(e), —P(═O)₂OR^(e), —NR^(b)R^(c),—NR^(b)S(═O)₂R^(e), —NR^(b)P(═O)₂R^(e), —S(═O)₂NR^(b)R^(c),—P(═O)₂NR^(b)R^(c), —C(═O)OR^(e), —C(═O)R^(a), —C(═O)NR^(b)R^(c),—OC(═O)R^(a), —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)OR^(e),—NR^(d)C(═O)NR^(b)R^(c), —NR^(d)S(═O)₂NR^(b)R^(c),—NR^(d)P(═O)₂NR^(b)R^(c), —NR^(b)C(═O)R^(a) or —NR^(b)P(═O)₂R^(e),wherein R^(a) is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle or aryl; R^(b), R^(c) and R^(d) are independentlyhydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said R^(b) andR^(c) together with the N to which they are bonded optionally form aheterocycle; and R^(e) is alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle or aryl. In the aforementioned exemplarysubstituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl,cycloalkenyl, heterocycle and aryl can themselves be optionallysubstituted.

Examples of substituents on alkenyl and alkynyl groups include, but arenot limited to, alkyl or substituted alkyl, as well as those groupsrecited as examples of alkyl substituents.

Examples of substituents on cycloalkyl groups include, but are notlimited to, nitro, cyano, alkyl or substituted alkyl, as well as thosegroups recited above as examples of alkyl substituents. Other examplesof substituents include, but are not limited to, spiro-attached or fusedcyclic substituents, for example, spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted.

Examples of substituents on cycloalkenyl groups include, but are notlimited to, nitro, cyano, alkyl or substituted alkyl, as well as thosegroups recited as examples of alkyl substituents. Other examples ofsubstituents include, but are not limited to, spiro-attached or fusedcyclic substituents, for examples spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted.

Examples of substituents on aryl groups include, but are not limited to,nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substitutedcycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groupsrecited above as examples of alkyl substituents. Other examples ofsubstituents include, but are not limited to, fused cyclic groups, suchas fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fusedaryl, where the aforementioned cycloalkyl, cylcoalkenyl, heterocycle andaryl substituents can themselves be optionally substituted. Still otherexamples of substituents on aryl groups (phenyl, as a non-limitingexample) include, but are not limited to, haloalkyl and those groupsrecited as examples of alkyl substituents.

Examples of substituents on heterocylic groups include, but are notlimited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, nitro, oxo (i.e., ═O), cyano, alkyl,substituted alkyl, as well as those groups recited as examples of alkylsubstituents. Other examples substituents on heterocyclic groupsinclude, but are not limited to, spiro-attached or fused cylicsubstituents at any available point or points of attachment, for examplespiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attachedheterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl,fused heterocycle and fused aryl, where the aforementioned cycloalkyl,cycloalkenyl, heterocycle and aryl substituents can themselves beoptionally substituted.

In certain embodiments, a heterocyclic group is substituted on carbon,nitrogen and/or sulfur at one or more positions. Examples ofsubstituents on nitrogen include, but are not limited to alkyl, aryl,aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl,alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfurinclude, but are not limited to, oxo and C₁₋₆alkyl. In certainembodiments, nitrogen and sulfur heteroatoms may independently beoptionally oxidized and nitrogen heteroatoms may independently beoptionally quaternized.

Exemplary substituents on ring groups, such as aryl, heteroaryl,cycloalkyl and heterocyclyl, include halogen, alkoxy and alkyl.

Exemplary substituents on alkyl groups include halogen and hydroxy.

A “halohydrocarbyl” as employed herein is a hydrocarbyl moiety, in whichfrom one to all hydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally optionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, dialkylamino (wherein each alkyl may be the same ordifferent), arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from within one of the specified groups or from within thecombination of all of the specified groups.

In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5- to 6-membered mono- and 9- to14-membered bi-cyclic moieties fused to the parent cyclic moiety to forma bi- or tri-cyclic fused ring system. Substituents on cyclic moietiesalso include 5- to 6-membered mono- and 9- to 14-membered bi-cyclicmoieties attached to the parent cyclic moiety by a covalent bond to forma bi- or tri-cyclic bi-ring system. For example, an optionallysubstituted phenyl includes, but is not limited to, the following:

An “unsubstituted” moiety (e.g., unsubstituted cycloalkyl, unsubstitutedheteroaryl, etc.) means a moiety as defined above that does not have anyoptional substituents.

A saturated, partially unsaturated or unsaturated three- toeight-membered carbocyclic ring is for example a four- toseven-membered, alternatively a five- or six-membered, saturated orunsaturated carbocyclic ring. Examples of saturated or unsaturatedthree- to eight-membered carbocyclic rings include phenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

A saturated, partially unsaturated or unsaturated three- toeight-membered heterocyclic ring contains at least one heteroatomselected from oxygen, nitrogen, and sulfur atoms. The saturated orunsaturated three- to eight-membered heterocyclic ring for examplecontains one or two heteroatoms with the remaining ring-constitutingatoms being carbon atoms. The saturated or unsaturated three- toeight-membered heterocyclic ring is alternatively a saturated orunsaturated four- to seven-membered heterocyclic ring, alternatively asaturated or unsaturated five- or six-membered heterocyclic ring.Examples of saturated or unsaturated three- to eight-memberedheterocyclic groups include thienyl, pyridyl, 1,2,3-triazolyl,imidazolyl, isoxazolyl, pyrazolyl, piperazinyl, piperazino, piperidyl,piperidino, morpholinyl, morpholino, homopiperazinyl, homopiperazino,thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl.

A saturated or unsaturated carboxylic and heterocyclic group maycondense with another saturated or heterocyclic group to form a bicyclicgroup, for example a saturated or unsaturated nine- to twelve-memberedbicyclic carbocyclic or heterocyclic group. Bicyclic groups includenaphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl,indolyl, and 1,2,3,4-tetrahydronaphthyl.

When a carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain, for example a C₁₋₃ alkylene chain. Carbocyclic orheterocyclic groups having this crosslinked structure includebicyclo[2.2.2]octanyl and norbornanyl.

The terms “kinase inhibitor” and “inhibitor of kinase activity”, and thelike, are used to identify a compound which is capable of interactingwith a kinase and inhibiting its enzymatic activity.

The term “inhibiting kinase enzymatic activity” is used to mean reducingthe ability of a kinase to transfer a phosphate group from a donormolecule, such as ATP, to a specific target molecule (substrate). Forexample, the inhibition of kinase activity may be at least about 10%. Insome embodiments of the invention, such reduction of kinase activity isat least about 25%, alternatively at least about 50%, alternatively atleast about 75%, and alternatively at least about 90%. In otherembodiments, kinase activity is reduced by at least 95% andalternatively by at least 99%. The IC₅₀ value is the concentration ofkinase inhibitor which reduces the activity of a kinase to 50% of theuninhibited enzyme.

The terms “inhibitor of VEGF receptor signaling” and “inhibitor of HGFreceptor signaling” are used to identify a compound having a structureas defined herein, which is capable, respectively, of interacting with aVEGF receptor and a HGF receptor and inhibiting the activity of the VEGFreceptor and the HGF receptor. In some embodiments, such reduction ofactivity is at least about 50%, alternatively at least about 75%, andalternatively at least about 90%. In other embodiments, activity isreduced by at least 95% and alternatively by at least 99%.

The term “inhibiting effective amount” is meant to denote a dosagesufficient to cause inhibition of kinase activity. The kinase may be ina cell, which in turn may be in a multicellular organism. Themulticellular organism may be, for example, a plant, a fungus or ananimal, for example a mammal and for example a human. The fungus may beinfecting a plant or a mammal, for example a human, and could thereforebe located in and/or on the plant or mammal. If the kinase is in amulticellular organism, the method according to this aspect of theinvention comprises the step of administering to the organism a compoundor composition according to the present invention.

In an exemplary embodiment, such inhibition is specific, i.e., thekinase inhibitor reduces the ability of a kinase to transfer a phosphategroup from a donor molecule, such as ATP, to a specific target molecule(substrate) at a concentration that is lower than the concentration ofthe inhibitor that is required to produce another, unrelated biologicaleffect. For example, the concentration of the inhibitor required forkinase inhibitory activity is at least 2-fold lower, alternatively atleast 5-fold lower, alternatively at least 10-fold lower, andalternatively at least 20-fold lower than the concentration required toproduce an unrelated biological effect.

The term “therapeutically effective amount” as employed herein is anamount of a compound of the invention, that when administered to apatient, elicits the desired therapeutic effect. The therapeutic effectis dependent upon the disease being treated and the results desired. Assuch, the therapeutic effect can be treatment of a disease-state.Further, the therapeutic effect can be inhibition of kinase activity.The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the disease state and its severity, the age of the patient to betreated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art.

In one embodiment, the therapeutic effect is inhibition of angiogenesis.The phrase “inhibition of angiogenesis” is used to denote an ability ofa compound according to the present invention to retard the growth ofblood vessels, preferably new blood vessels contacted with the inhibitoras compared to blood vessels not contacted. In one embodiment,angiogenesis is tumor angiogenesis. The phrase “tumor angiogenesis” isintended to mean the proliferation of blood vessels that penetrate intoa cancerous growth, such as a tumor. In another embodiment, angiogenesisis abnormal blood vessel formation in the eye.

In an exemplary embodiment, angiogenesis is retarded by at least 25% ascompared to angiogenesis of non-contacted blood vessels, alternativelyat least 50%, alternatively at least 75%, alternatively at least 90%,alternatively at least 95%, and alternatively, at least 99%.Alternatively, angiogenesis is inhibited by 100% (i.e., the bloodvessels do not increase in size or number). In certain embodiments, thephrase “inhibition of angiogenesis” includes regression in the number orsize of blood vessels, as compared to non-contacted blood vessels. Thus,a compound according to the invention that inhibits angiogenesis mayinduce blood vessel growth retardation, blood vessel growth arrest, orinduce regression of blood vessel growth.

In another embodiment, the therapeutic effect is treatment of anophthalmic diseases, disorder or condition. The phrase “treatment of anophthalmic disease or disorder” is intended to mean the ability of acompound according to the present invention to treat an exudative and/orinflammatory ophthalmic disease or disorder, a disorder related toimpaired retinal vessel permeability and/or integrity, a disorderrelated to retinal microvessel rupture leading to focal hemorrhage, adisease of the back of the eye, a retinal disease, or a disease of thefront of the eye, or other ophthalmic disease, disorder or condition.

In one embodiment, the ophthalmic disease, disorder or conditionincludes but is not limited to Age Related Macular Degeneration (ARMD),exudative macular degeneration (also known as “wet” or neovascularage-related macular degeneration (wet-AMD), macular oedema, ageddisciform macular degeneration, cystoid macular oedema, palpebraloedema, retinal oedema, diabetic retinopathy, Acute MacularNeuroretinopathy, Central Serous Chorioretinopathy, chorioretinopathy,Choroidal Neovascularization, neovascular maculopathy, neovascularglaucoma, obstructive arterial and venous retinopathies (e.g. RetinalVenous Occlusion or Retinal Arterial Occlusion), Central Retinal VeinOcclusion, Disseminated Intravascular Coagulopathy, Branch Retinal VeinOcclusion, Hypertensive Fundus Changes, Ocular Ischemic Syndrome,Retinal Arterial Microaneurysms, Coat's Disease, ParafovealTelangiectasis, Hemi-Retinal Vein Occlusion, Papillophlebitis, CentralRetinal Artery Occlusion, Branch Retinal Artery Occlusion, CarotidArtery Disease (CAD), Frosted Branch Angitis, Sickle Cell Retinopathyand other Hemoglobinopathies, Angioid Streaks, macular oedema occurringas a result of aetiologies such as disease (e.g. Diabetic MacularOedema), eye injury or eye surgery, retinal ischemia or degenerationproduced for example by injury, trauma or tumours, uveitis, iritis,retinal vasculitis, endophthalmitis, panophthalmitis, metastaticophthalmia, choroiditis, retinal pigment epithelitis, conjunctivitis,cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar opticneuritis, keratitis, blepharitis, exudative retinal detachment, cornealulcer, conjunctival ulcer, chronic nummular keratitis, Thygesonkeratitis, progressive Mooren's ulcer, an ocular inflammatory diseasecaused by bacterial or viral infection or by an ophthalmic operation, anocular inflammatory disease caused by a physical injury to the eye, anda symptom caused by an ocular inflammatory disease including itching,flare, oedema and ulcer, erythema, erythema exsudativum multiforme,erythema nodosum, erythema annulare, scleroedema, dermatitis,angioneurotic oedema, laryngeal oedema, glottic oedema, subglotticlaryngitis, bronchitis, rhinitis, pharyngitis, sinusitis, laryngitis orotitis media.

In another embodiment, the ophthalmic disease, disorder or conditionincludes but is not limited to age-related macular degeneration,diabetic retinopathy, retinal edema, retinal vein occlusion, neovascularglaucoma, retinopathy of prematurity, pigmentary retinal degeneration,uveitis, corneal neovascularization or proliferative vitreoretinopathy.

In another embodiment, the ophthalmic disease, disorder or condition isage-related macular degeneration, diabetic retinopathy or retinal edema.

In another embodiment, the therapeutic effect is inhibition of retinalneovascularization. The phrase “inhibition of retinalneovascularization” is intended to mean the ability of a compoundaccording to the present invention to retard the growth of blood vesselsin the eye, for example new blood vessels originating from retinalveins, for example, to retard the growth of new blood vesselsoriginating from retinal veins and extending along the inner (vitreal)surface of the retina.

In an exemplary embodiment, retinal neovascularization is retarded by atleast 25% as compared to retinal neovascularization of non-contactedblood vessels, alternatively at least 50%, alternatively at least 75%,alternatively at least 90%, alternatively at least 95%, andalternatively, at least 99%. Alternatively, retinal neovascularizationis inhibited by 100% (i.e., the blood vessels do not increase in size ornumber). In certain embodiments, the phrase “inhibition of retinalneovascularization” includes regression in the number or size of bloodvessels, as compared to non-contacted blood vessels. Thus, a compoundaccording to the invention that inhibits retinal neovascularization mayinduce blood vessel growth retardation, blood vessel growth arrest, orinduce regression of blood vessel growth.

In another embodiment, the therapeutic effect is inhibition of cellproliferation. The phrase “inhibition of cell proliferation” is used todenote an ability of a compound according to the present invention toretard the growth of cells contacted with the inhibitor as compared tocells not contacted. An assessment of cell proliferation can be made bycounting contacted and non-contacted cells using a Coulter Cell Counter(Coulter, Miami, Fla.) or a hemacytometer. Where the cells are in asolid growth (e.g., a solid tumor or organ), such an assessment of cellproliferation can be made by measuring the growth with calipers orcomparing the size of the growth of contacted cells with non-contactedcells.

In an exemplary embodiment, growth of cells contacted with the inhibitoris retarded by at least 25% as compared to growth of non-contactedcells, alternatively at least 50%, alternatively at least 75%,alternatively at least 90%, alternatively at least 95%, andalternatively, at least 99%. Alternatively, cell proliferation isinhibited by 100% (i.e., the contacted cells do not increase in number).In certain embodiments, the phrase “inhibition cell proliferation”includes a reduction in the number or size of contacted cells, ascompared to non-contacted cells. Thus, a compound according to theinvention that inhibits cell proliferation in a contacted cell mayinduce the contacted cell to undergo growth retardation, to undergogrowth arrest, to undergo programmed cell death (i.e., to apoptose), orto undergo necrotic cell death.

In some embodiments, the contacted cell is a neoplastic cell. The term“neoplastic cell” is used to denote a cell that shows aberrant cellgrowth. In certain embodiments, the aberrant cell growth of a neoplasticcell is increased cell growth. A neoplastic cell may be a hyperplasticcell, a cell that shows a lack of contact inhibition of growth in vitro,a benign tumor cell that is incapable of metastasis in vivo, or a cancercell that is capable of metastasis in vivo and that may recur afterattempted removal. The term “tumorigenesis” is used to denote theinduction of cell proliferation that leads to the development of aneoplastic growth.

In some embodiments, the contacted cell is in an animal. Thus, theinvention provides a method for treating a cell proliferative disease orcondition in an animal, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orcomposition of the invention. In certain exemplary embodiments, theanimal is a mammal, for example a domesticated mammal. In someembodiments, the animal is a human.

The term “cell proliferative disease or condition” is meant to refer toany condition characterized by aberrant cell growth, preferablyabnormally increased cellular proliferation. Examples of such cellproliferative diseases or conditions amenable to inhibition andtreatment include, but are not limited to, cancer. Examples ofparticular types of cancer include, but are not limited to, breastcancer, lung cancer, colon cancer, rectal cancer, bladder cancer,prostate cancer leukemia and renal cancer. In particular embodiments,the invention provides a method for inhibiting neoplastic cellproliferation in an animal comprising administering to an animal havingat least one neoplastic cell present in its body a therapeuticallyeffective amount of a compound of the invention.

The term “patient” as employed herein for the purposes of the presentinvention includes humans and other animals, for example mammals, andother organisms. Thus the compounds, compositions and methods of thepresent invention are applicable to both human therapy and veterinaryapplications. In certain embodiments the patient is a mammal, forexample a human.

The terms “treating”, “treatment”, or the like, as used herein coversthe treatment of a disease-state in an organism, and includes at leastone of: (i) preventing the disease-state from occurring, in particular,when such animal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (ii) inhibiting the disease-state, i.e.,partially or completely arresting its development; (iii) relieving thedisease-state, i.e., causing regression of symptoms of thedisease-state, or ameliorating a symptom of the disease; and (iv)reversal or regression of the disease-state, preferably eliminating orcuring of the disease. In certain embodiments of the present inventionthe organism is an animal, for example a mammal, for example a primate,for example a human. As is known in the art, adjustments for systemicversus localized delivery, age, body weight, general health, sex, diet,time of administration, drug interaction, the severity of the condition,etc., may be necessary, and will be ascertainable with routineexperimentation by one of ordinary skill in the art. In certainembodiments, the terms “treating”, “treatment”, or the like, as usedherein covers the treatment of a disease-state in an organism andincludes at least one of (ii), (iii) and (iv) above.

Administration may be by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain embodiments, compounds of theinvention are administered intravenously in a hospital setting. Incertain other embodiments, administration may be by the oral route.

Examples of routes of administration for ophthalmic diseases, disordersand conditions include but are not limited to, systemic, periocular,retrobulbar, intracanalicular, intravitral injection, topical (forexample, eye drops), subconjunctival injection, subtenon, transcleral,intracameral, subretinal, electroporation, and sustained-releaseimplant. Other routes of administration other injection sites or otherforms of administration for ophthalmic situations will be known orcontemplated by one skilled in the art and are intended to be within thescope of the present invention.

In certain embodiments of the present invention, routes ofadministration for ophthalmic diseases, disorders and conditions includetopical, subconjunctival injection, intravitreal injection, or otherocular routes, systemically, or other methods known to one skilled inthe art to a patient following ocular surgery.

In certain other embodiments of the present invention, routes ofadministration for ophthalmic diseases, disorders and conditions includetopical, intravitreal, transcleral, periocular, conjunctival, subtenon,intracameral, subretinal, subconjunctival, retrobulbar, orintracanalicular.

In certain other embodiments of the present invention, routes ofadministration for ophthalmic diseases, disorders and conditions includetopical administration (for example, eye drops), systemic administration(for example, oral or intravenous), subconjunctival injection,periocular injection, intravitreal injection, and surgical implant.

In certain other embodiments of the present invention, routes ofadministration for ophthalmic diseases, disorders and conditions includeintravitreal injection, periocular injection, and sustained-releaseimplant.

In certain other embodiments of the present invention, an intraocularinjection may be into the vitreous (intravitreal), under the conjunctiva(subconjunctival), behind the eye (retrobulbar), into the sclera, underthe Capsule of Tenon (sub-Tenon), or may be in a depot form.

The compounds of the present invention form salts which are also withinthe scope of this invention. Reference to a compound of the invention,for example a compound of Formula (I), herein is understood to includereference to salts thereof, unless otherwise indicated.

The term “salt(s)”, as employed herein, denotes acidic and/or basicsalts formed with inorganic and/or organic acids and bases. In addition,when a compound of the present invention contains both a basic moiety,such as but not limited to a pyridine or imidazole, and an acidic moietysuch as but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. Pharmaceutically acceptable (i.e., non-toxic (exhibiting minimalor no undesired toxicological effects), physiologically acceptable)salts are preferred, although other salts are also useful, e.g., inisolation or purification steps which may be employed duringpreparation. Salts of the compounds of the invention may be formed, forexample, by reacting a compound of the present invention with an amountof acid or base, such as an equivalent amount, in a medium such as onein which the salts precipitates or in an aqueous medium followed bylyophilization.

The compounds of the present invention which contain a basic moiety,such as but not limited to an amine or a pyridine or imidazole ring, mayform salts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfanotes(e.g., 2-hydroxyethanesulfonates), lactates, maleates,methanesulfonates, naphthalenesulfonates (e.g.,2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates,persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates, tartrates,thiocyanates, toluenesulfonates such as tosylates, undecanoates, and thelike.

The compounds of the present invention which contain an acidic moiety,such as but not limited to a carboxylic acid, may form salts with avariety of organic and inorganic bases. Exemplary basic salts includeammonium salts, alkali metal salts such as sodium, lithium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases (for example, organic amines) such asbenzathines, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibuty and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

As used herein, the term “pharmaceutically acceptable salts” is intendedto mean salts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to, salts formed with inorganic acids (for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, andthe like), and salts formed with organic acids such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamicacid, naphthalenesulfonic acid, naphthalenedisulfonic acid,methanesulfonic acid, p-toluenesulfonic acid and polygalacturonic acid.Other salts include pharmaceutically acceptable quaternary salts knownby those skilled in the art, which specifically include the quaternaryammonium salt of the formula —NR+Z—, wherein R is hydrogen, alkyl, orbenzyl, and Z is a counterion, including chloride, bromide, iodide,—O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, orcarboxylate (such as benzoate, succinate, acetate, glycolate, maleate,malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

Another aspect of the invention provides compositions including acompound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt,complex or prodrug of a compound according to the present invention asdescribed herein, or a racemic mixture, scalemic mixture, diastereomer,enantiomer or tautomer thereof. For example, in one embodiment of theinvention, a composition comprises a compound, N-oxide, hydrate,solvate, pharmaceutically acceptable salt, complex or prodrug of acompound according to the present invention as described herein presentin at least about 30% enantiomeric or diastereomeric excess. In certainembodiments of the invention, the compound, N-oxide, hydrates, solvate,pharmaceutically acceptable salt, complex or prodrug is present in atleast about 50%, at least about 80%, or even at least about 90%enantiomeric or diastereomeric excess. In certain other embodiments ofthe invention, the compound, N-oxide, hydrate, solvate, pharmaceuticallyacceptable salt, complex or prodrug is present in at least about 95%,alternatively at least about 98% and alternatively at least about 99%enantiomeric or diastereomeric excess. In other embodiments of theinvention, a compound, N-oxide, hydrate, solvate, pharmaceuticallyacceptable salt, complex or prodrug is present as a substantiallyracemic mixture.

Some compounds of the invention may have chiral centers and/or geometricisomeric centers (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, enantiomeric, diastereoisomericand geometric isomers. The invention also comprises all tautomeric formsof the compounds disclosed herein. Where compounds of the inventioninclude chiral centers, the invention encompasses the enantiomericallyand/or diasteromerically pure isomers of such compounds, theenantiomerically and/or diastereomerically enriched mixtures of suchcompounds, and the racemic and scalemic mixtures of such compounds. Forexample, a composition may include a mixture of enantiomers ordiastereomers of a compound of Formula (I) in at least about 30%diastereomeric or enantiomeric excess. In certain embodiments of theinvention, the compound is present in at least about 50% enantiomeric ordiastereomeric excess, in at least about 80% enantiomeric ordiastereomeric excess, or even in at least about 90% enantiomeric ordiastereomeric excess. In certain embodiments of the invention, thecompound is present in at least about 95%, alternatively in at leastabout 98% enantiomeric or diastereomeric excess, and alternatively in atleast about 99% enantiomeric or diastereomeric excess.

The chiral centers of the present invention may have the S or Rconfiguration. The racemic forms can be resolved by physical methods,such as, for example, fractional crystallization, separation orcrystallization of diastereomeric derivates or separation by chiralcolumn chromatography. The individual optical isomers can be obtainedeither starting from chiral precursors/intermediates or from theracemates by any suitable method, including without limitation,conventional methods, such as, for example, salt formation with anoptically active acid followed by crystallization.

The present invention also includes prodrugs of compounds of theinvention. The term “prodrug” is intended to represent a compoundcovalently bonded to a carrier, which prodrug is capable of releasingthe active ingredient when the prodrug is administered to a mammaliansubject. Release of the active ingredient occurs in vivo. Prodrugs canbe prepared by techniques known to one skilled in the art. Thesetechniques generally modify appropriate functional groups in a givencompound. These modified functional groups however regenerate originalfunctional groups by routine manipulation or in vivo. Prodrugs ofcompounds of the invention include compounds wherein a hydroxy, amino,carboxylic, or a similar group is modified. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy or amino functional groups in compounds of the presentinvention), amides (e.g., trifluoroacetylamino, acetylamino, and thelike), and the like.

The compounds of the invention may be administered as is or as aprodrug, for example in the form of an in vivo hydrolyzable ester or invivo hydrolyzable amide. An in vivo hydrolyzable ester of a compound ofthe invention containing carboxy or hydroxy group is, for example, apharmaceutically acceptable ester which is hydrolyzed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include C₁-C₆alkoxymethylesters (e.g., methoxymethyl), C₁-C₆alkanoyloxymethyl esters (e.g., forexample pivaloyloxymethyl), phthalidyl esters,C₃-C₈cycloalkoxycarbonyloxy-C₁-C₆alkyl esters (e.g.,1-cyclohexylcarbonyloxyethyl); 1,3-dioxolen-2-onylmethyl esters (e.g.,5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆alkoxycarbonyloxyethylesters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at anyappropriate carboxy group in the compounds of this invention.

An in vivo hydrolyzable ester of a compound of the invention containinga hydroxy group includes inorganic esters such as phosphate esters andα-acyloxyalkyl ethers and related compounds which as a result of the invivo hydrolysis of the ester breakdown to give the parent hydroxy group.Examples of α-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolyzableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN—(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),N,N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.A suitable value for an in vivo hydrolyzable amide of a compound of theinvention containing a carboxy group is, for example, a N—C₁-C₆alkyl orN,N-di-C₁-C₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Upon administration to a subject, the prodrug undergoes chemicalconversion by metabolic or chemical processes to yield a compound of thepresent invention, or, for example, a salt and/or solvate thereof.Solvates of the compounds of the present invention include, for example,hydrates.

Throughout the specification, embodiments of one or more chemicalsubstituents are identified. Also encompassed are combinations ofvarious embodiments. For example, the invention describes certainembodiments of D in the compounds and describes certain embodiments ofgroup G. Thus, as an example, also contemplated as within the scope ofthe invention are compounds in which examples of D are as described andin which examples of group G are as described.

Compounds

According to one embodiment, the invention provides compounds of Formula(I):

-   and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,    prodrugs and complexes thereof, and racemic and scalemic mixtures,    diastereomers and enantiomers thereof, wherein,-   D is selected from the group consisting of an aromatic,    heteroaromatic, cycloalkyl or heterocyclic ring system, each of    which is optionally substituted with 1 to 5 independently selected    R³⁸;-   M is an optionally substituted fused heterocyclic moiety;-   Z is selected from the group consisting of covalent bond, —O—,    —O—CH₂—, —CH₂—O—, —S(O)₀₋₂—, —CH₂—, —N(R⁵)—, —N(R⁵)—CH₂— and    —CH₂—N(R⁵)—;-   Ar is a 5 to 7 membered cycloalkyl, aromatic, heterocyclic or    heteroaromatic ring system, any of which is optionally substituted    with 0 to 4 R² groups; and-   G is a group B-L-T, wherein-   B is selected from the group consisting of absent, —N(R¹³)—,    —N(SO₂R¹³)—, —O—, —S(O)₀₋₂ and —C(═O)—;-   L is selected from the group consisting of absent, —C(═S)N(R¹³)—,    —C(═NR¹⁴)N(R¹³)—, —SO₂N(R¹³)—, —SO₂—, —C(═O)N(R¹³)—, —N(R¹³)—,    —C(═O)C₁₋₂alkyl-N(R¹³)—, —N(R¹³)C₁₋₂alkyl-C(═O)—,    —C(═O)C₀₋₁alkyl-C(═O)N(R¹³)—, —C₀₋₄alkylene,    —C(═O)C₀₋₁alkyl-C(═O)OR³—, —C(═NR¹⁴)—C₀₋₁alkyl-C(═O)—, —C(═O)—,    —C(═O)C₀₋₁alkyl-C(═O)— and an optionally substituted four to    six-membered heterocyclyl containing between one and three annular    heteroatoms including at least one nitrogen, wherein an alkyl group    of the aforementioned L group is optionally substituted; and-   T is selected from the group consisting of —H, —R¹³, —C₀₋₅alkyl,    —C₀₋₅alkyl-Q, —O—C₀₋₅alkyl-Q, —C₀₋₅alkyl-O-Q, —N(R¹³)—C₀₋₅alkyl-Q,    —C₀₋₅alkyl-SO₂—C₀₋₅alkyl-Q, —C(═O)—C₀₋₅alkyl-Q, —C(═S)—C₀₋₅-alkyl-Q,    —C(═NR¹⁴)—C₀₋₅-alkyl-Q, —C₀₋₅alkyl-N(R¹³)-Q,    —C(═O)—N(R¹³)—C₀₋₅alkyl-Q, —C(═S)—N(R¹³)—C₀₋₅alkyl-Q,    —C(═NR⁴)—N(R¹³)—C₀₋₅alkyl-Q, —(C₀₋₅alkyl-C(O))₀₋₁—C₀₋₅alkyl-Q    wherein each C₀₋₅alkyl is optionally substituted;-   or G is

-   or G is selected from the group consisting of:

-   wherein-   each R³⁸ is independently selected from the group consisting of    halo, optionally substituted C₁-C₆ alkyl, —C(O)NR³⁶R³⁹,    —C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆    alkyl), —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,    —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,    —(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,    —NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and    —NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂,    —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)SO₍₀₋₂₎(CH₂)_(i)[O(CH₂)_(i)]_(j)(CH₂)_(j)R⁹⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(j)R¹⁰⁰-   wherein each j is an integer independently ranging from 0 to 4 and    alternatively 1-2, n is an integer ranging from 0 to 6, x is an    integer ranging from 1-6 and alternatively 2-3, each i is an integer    independently ranging from 1 to 3, and the —(CH₂)_(i)— and    —(CH₂)_(n)— moieties of the foregoing R³⁸ groups are optionally    substituted, for example with C₁-C₆alkyl, and optionally include a    carbon-carbon double or triple bond where n is an integer between 2    and 6;-   R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl,    C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered    heterocyclyl) and —(CH₂)_(n)A⁴R³⁷, wherein each n is an integer    independently ranging from 0 to 6, A⁴ is selected from the group    consisting of O, S, SO, SO₂, and the alkyl, cycloalkyl, aryl and    heterocyclyl moieties of the foregoing R³⁶ groups are optionally    substituted, with the proviso that when R³⁶ and R³⁹ are both    attached to the same nitrogen, then R³⁶ and R³⁹ are not both bonded    to the nitrogen directly through an oxygen;-   each R³⁷ and R⁴¹ is independently selected from H, —O—C₁-C₆ alkyl,    —O—C₃-C₁₀ cycloalkyl, —O—-(CH₂)_(n)(C₆-C₁₀ aryl), —O—(CH₂)_(n)(5-10    membered heterocyclyl), optionally substituted C₁-C₆ alkyl,    optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆    alkynyl, optionally substituted C₃-C₁₀ cycloalkyl, optionally    substituted —O—(CH₂)_(n)A⁴-C₁-C₆ alkyl, optionally substituted    —O—(CH₂)_(n)A⁴-C₂-C₆ alkenyl, optionally substituted    —O—(CH₂)_(n)A⁴-C₂-C₆ alkynyl and optionally substituted    —O—(CH₂)_(n)A⁴-C₃-C₁₀cyclaoalkyl;-   R³⁹ is selected from the group consisting of H, —OH, C₁-C₆ alkyl,    —C(O)—C₁-C₆alkyl, —SO₂—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl-aryl and a    protecting group used to protect secondary amino groups, with the    proviso that when R³⁶ and R³⁹ are both attached to the same    nitrogen, then R³⁶ and R³⁹ are not both bonded to the nitrogen    directly through an oxygen;-   each R⁴⁰ is independently selected from H, C₁-C₁₀ alkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10    membered heterocyclyl), wherein n is an integer ranging from 0 to 6;-   R⁹⁹ at each occurrence is independently selected from the group    consisting of —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³,    —NR³R⁴, —S(O)₀₋₂R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³,    —N(R³)C(O)R³, —N(R³)CO₂R³, P(═O)(OH)₂, —P(═O)(C₁-C₆alkyl)₂,    —SO₃H—C(O)R³, C₁-C₄ alkoxy, C₁-C₄ alkylthio, —O(CH₂)₀₋₆aryl,    —O(CH₂)₀₋₆heteroaryl, —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), -,    C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², wherein    the aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl    are optionally substituted;-   R¹⁰⁰ is a 12 to 24-membered optionally substituted heteroalicyclic    macrocycle containing 4 to 8 oxygen atoms, for example 15-crown-5,    18-crown-6, or 21-crown-7;-   R⁵ is selected from the group consisting of H, an optionally    substituted (C₁-C₅)acyl and C₁-C₆ alkyl-O—C(O), wherein C₁-C₆ alkyl    is optionally substituted;-   R² at each occurrence is independently selected from the group    consisting of —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³,    —NR³R⁴, —S(O)₀₋₂R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³,    —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, C₁-C₄ alkoxy, C₁-C₄ alkylthio,    —O(CH₂)₀₋₆aryl, —O(CH₂)₀₋₆heteroaryl, —(CH₂)₀₋₅(aryl),    —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    —CH₂(CH₂)₀₋₄-T², wherein the aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆    alkenyl, and C₂-C₆ alkynyl are optionally substituted;-   T² is selected from the group consisting of —OH, —OMe, —OEt, —NH₂,    —NHMe, —NMe₂, —NHEt and —NEt₂;-   each R³ is independently selected from the group consisting of —H    and R⁴;-   R⁴ is selected from the group consisting of a (C₁-C₆)alkyl, an aryl,    a lower arylalkyl, a heterocyclyl and a lower heterocyclylalkyl,    each of which is optionally substituted, or-   R³ and R⁴, taken together with a common nitrogen to which they are    attached, form an optionally substituted five- to seven-membered    heterocyclyl, the optionally substituted five- to seven-membered    heterocyclyl optionally containing at least one additional annular    heteroatom selected from the group consisting of N, O, S and P;-   each R¹³ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³,    —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³,    —N(R³)CO₂R³, —C(O)R³, —C(O)SR³, C₁-C₄ alkoxy, C₁-C₄ alkylthio,    —O(CH₂)₀₋₆aryl, —O(CH₂)₀₋₆heteroaryl, —(CH₂)₀₋₅(aryl),    —(CH₂)₀₋₅(heteroaryl), —(CH₂)₀₋₅(cycloalkyl), C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted    C₁₋₄ alkylcarbonyl, and a saturated or unsaturated three- to    seven-membered carboxyclic or heterocyclic group, wherein the aryl,    heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    optionally substituted;-   two R¹³, together with the atom or atoms to which they are attached,    can combine to form a heteroalicyclic optionally substituted with    between one and four of R⁶⁰, wherein the heteroalicyclic can have up    to four annular heteroatoms, and the heteroalicyclic can have an    aryl or heteroaryl fused thereto, in which case the aryl or    heteroaryl is optionally substituted with an additional one to four    of R⁶⁰;-   R¹⁴ is selected from the group —H, —NO₂, —NH₂, —N(R³)R⁴, —CN, —OR³,    an optionally substituted (C₁-C₆)alkyl, an optionally substituted    heteroalicyclylalkyl, an optionally substituted aryl, an optionally    substituted arylalkyl and an optionally substituted heteroalicyclic,-   R⁶⁰ is selected from the group consisting of —H, halogen,    trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³,    —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³,    an optionally substituted (C₁-C₆)alkyl, an optionally substituted    aryl, an optionally substituted heteroarylalkyl and an optionally    substituted arylalkyl; or-   two R⁶⁰, when attached to a non-aromatic carbon, can be oxo;-   Q is C₁-C₆alkyl or a three- to ten-membered ring system, optionally    substituted with between zero and four of R²⁰;-   each R²⁰ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —O— trihalomethyl, oxo, —CN, —NO₂, —NH₂,    —OR³, —OCF₃, —NR³R⁴, —S(O)₀₋₂R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³,    —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)C(O)OR³, —C(O)R³, —C(O)SR³, C₁-C₄    alkoxy, C₁-C₄ alkylthio, —O(CH₂)₀₋₆aryl, —O(CH₂)₀₋₆heteroaryl,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, C₁₋₄ alkoxy, an amino optionally substituted by C₁₋₄    alkyl optionally substituted by C₁₋₄ alkoxy and a saturated or    unsaturated three- to seven-membered carboxyclic or heterocyclic    group and wherein the aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl,    and C₂-C₆ alkynyl are optionally substituted;-   L¹ is selected from the group consisting of O, S and N(R¹⁴);-   L² is selected from the group consisting of —C(O)—, —C(S)—, —C(NH)—,    >C═N(C₁-C₆ alkyl) and —CH₂—;-   L³ is selected from the group consisting of —CH—, —C(C₁-C₆ alkyl)-    and N;-   L⁴ is selected from the group consisting of —CH— and N;-   n1 is an integer from 0 to 5;-   each X is independently selected from the group consisting of O, S,    NH, N-alkyl, N—OH, N—O-alkyl and NCN;-   R¹¹ and R¹² are independently selected from the group consisting of    H, C₁-C₆alkyl, halo, cyano and nitro, wherein the alkyl is    optionally substituted; or-   R¹¹ and R¹², taken together with the atom to which they are    attached, form a C₃-C₇cycloalkyl;-   E is selected from the group consisting of O, S, —CH₂—,    —CH(C₁-C₆alkyl), —N(H)—, —N(C₁-C₆alkyl)-, —CH₂N(H)— and —N(H)CH₂—;-   R^(11a) and R^(12a) are independently selected from the group    consisting of H, halogen, —OH, unsubstituted —O—(C₁-C₆alkyl),    substituted —O—(C₁-C₆alkyl), unsubstituted —O-(cycloalkyl),    substituted —O-(cycloalkyl), unsubstituted —NH(C₁-C₆alkyl),    substituted —NH(C₁-C₆alkyl), —NH₂, —SH, unsubstituted    —S—(C₁-C₆alkyl), substituted —S—(C₁-C₆alkyl), unsubstituted    C₁-C₆alkyl and substituted C₁-C₆alkyl; or-   R^(11a) and R^(12a) taken together with the atom to which they are    attached form a C₃-C₇ ring system, wherein said ring system is    optionally substituted;-   each R^(13a) is independently selected from the group consisting of    H, C₁-C₆alkyl, substituted C₁-C₆alkyl, cycloalkyl, substituted    cycloalkyl, OH, unsubstituted —O—(C₁-C₆alkyl), substituted    —O—(C₁-C₆alkyl); or-   R^(12a) and R^(13a) taken together with the atoms to which they are    attached optionally form a 4 to 8 membered cycloalkyl or    heterocyclic ring system, which ring system is optionally    substituted;-   R^(14a), R^(15a), R^(16a) and R^(17a) are independently selected    from the group consisting of —H, halogen, trihalomethyl,    —O-trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —OCF₃, —NR³R⁴, —S(O)₀₋₂R³,    —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³,    —N(R³)C(O)OR³, —C(O)R³, —C(O)SR³, C₁-C₄ alkoxy, C₁-C₄ alkylthio,    —O(CH₂)_(n)aryl, —O(CH₂)_(n)heteroaryl, (CH₂)₀₋₅(aryl),    —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄ alkylcarbonyl, C₁₋₄    alkoxy, an amino optionally substituted by C₁₋₄ alkyl optionally    substituted by C₁₋₄ alkoxy and a saturated or unsaturated three- to    seven-membered carboxyclic or heterocyclic group, wherein n is an    integer ranging from 0 to 6, and the aryl, heteroaryl, C₁-C₆ alkyl,    C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted; or-   R^(13a) and R^(14a) taken together with the atoms to which they are    attached optionally form a 4 to 8 membered cycloalkyl or    heterocyclic ring system, which ring system is optionally    substituted;-   R^(18a) and R^(19a) are independently selected from the group    consisting of H, OH, halogen, NO₂, unsubstituted —O—(C₁-C₆alkyl),    substituted —O—(C₁-C₆alkyl), CH₃, CH₂F, CHF₂, CF₃, CN, C₁-C₆alkyl,    substituted C₁-C₆alkyl, partially fluorinated C₁-C₆alkyl,    per-fluorinated C₁-C₆alkyl, heteroalkyl, substituted heteroalkyl and    —SO₂(C₁-C₆alkyl); or-   R^(18a) and R^(19a) together with the atom to which they are    attached form a 3 to 6 membered cycloalkyl or heterocycle, each of    which is optionally substituted with 1 to 4 halo, for example F;-   W is selected from the group consisting of H, alkyl, alkenyl,    alkynyl, —(CH₂)₀₋₅(five- to ten-membered cycloalkyl),    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heterocylic) and —(CH₂)₀₋₅(heteroaryl),    each of which is optionally substituted; and-   is a single or double bond;-   X¹ is selected from the group consisting of O, S, CH₂, N—CN,    N—O-alkyl, NH and N(C₁-C₆alkyl) when    is a double bond, or-   X¹ is selected from the group consisting of H, halogen,    trihaloalkyl, alkyl, alkenyl, alkynyl, CN, alkoxy, NH(alkyl) and    alkyl-thio, when    is a single bond;-   L^(a) and L^(1a) are independently selected from the group    consisting of —CH—, N, —C(halogen)- and —C(C₁-C₆alkyl)-;-   L^(2a) and L^(3a) are independently selected from the group    consisting of CH, CH₂, N, O and S;-   L^(4a) is selected from the group consisting of absent, CH, CH₂, N,    O and S; and the group

-   is aromatic or non-aromatic, provided that two 0 are not adjacent to    each other;-   K and K¹ are independently selected from the group consisting of    —C(O)—, —C(S)—, —C(NH)—, —C(NCN)— and —C(R^(18a)R^(19a))—;-   U is selected from the group consisting of O, S, SO₂, NH, and    N(C₁-C₆alkyl), wherein the C₁-C₆alkyl is optionally substituted with    a substituent selected from the group consisting of —OH, -alkoxy,    amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,

-   U¹ is a ring system selected from the group consisting of    cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted    heterocyclyl, aryl, substituted aryl, heteroaryl and substituted    heteroaryl;-   E¹ is selected from the group consisting of —N(H)—, —N(C₁-C₆alkyl)-,    —CH₂N(H)— and —N(H)CH₂—;-   E² is selected from the group consisting of —N(H)—, —N(C₁-C₆alkyl)-,    —CH₂N(H)— and —N(H)CH₂—;-   X² is selected from the group consisting of O, S, NH, NOH, NOMe,    NOEt and NCN; and-   n₂ is 0, 1, 2, 3 or 4.

In one embodiment of the compounds according to the present invention Dis an aromatic or heteroaromatic ring system, each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ groups.

In another embodiment according to the present invention, D issubstituted with one R³⁸ group.

In another embodiment according to the present invention, D is a 5- or6-membered aromatic or 5- or 6-membered heteroaromatic ring system, eachof which is optionally substituted with 1 to 5 independently selectedR³⁸ groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ groups.

In another embodiment according to the present invention, D is a6-membered aromatic or 6-membered heteroaromatic ring system, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ groups.

In another embodiment according to the present invention, D is a6-membered aromatic ring system, optionally substituted with 1 to 5independently selected R³⁸ groups, alternatively 1 to 3 independentlyselected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸groups.

In another embodiment according to the present invention, D is a6-membered heteroaromatic ring system, optionally substituted with 1 to5 independently selected R³⁸ groups, alternatively 1 to 3 independentlyselected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸groups.

According to another embodiment of the present invention, D is selectedfrom the group consisting of

wherein the members of said group are optionally substituted with 1 to 5independently selected R³⁸ groups, alternatively 1 to 3 independentlyselected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸groups.

According to another embodiment of the present invention, D is selectedfrom the group consisting of

wherein the members of said group are optionally substituted with 1 to 5independently selected R³⁸ groups, alternatively 1 to 3 independentlyselected R³⁸ groups, and alternatively 1 or 2 independently selected R³⁸groups.

According to another embodiment of the present invention, D is phenyl,pyridyl, furanyl, imidazolyl, tetrahydropyridyl, thienyl, pyrazolyl,each of which is optionally substituted with 1 to 5 independentlyselected R³⁸ groups, alternatively 1 to 3 independently selected R³⁸groups, and alternatively 1 or 2 independently selected R³⁸ groups.

In another embodiment according to the present invention, D is phenyl,optionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ groups.

In another embodiment according to the present invention, D is pyridyl,optionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ groups.

In another embodiment according to the present invention, D is phenyl,optionally substituted with one R³⁸.

In another embodiment according to the present invention, D is pyridyl,optionally substituted with one R³⁸.

In another embodiment according to the present invention, D is phenyl,substituted with one R³⁸.

In another embodiment according to the present invention, D is pyridyl,substituted with one R³⁸.

In another embodiment according to the present invention, D isimidazolyl, substituted with one R³⁸.

In another embodiment of the present invention, each R³⁸ isindependently selected from the group consisting of —C(O)NR³⁶R³⁹,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ and —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R¹⁶.

In another embodiment of the present invention each R³⁸ is independentlyselected from the group consisting of halo, optionally substituted C₁-C₆alkyl, —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In another embodiment of the present invention, R³⁶ is selected from thegroup consisting of H, —OH, C₁-C₆ alkyl and —(CH₂)_(n)A⁴R³⁷, forexample, —R³⁶ is (CH₂)_(n)OR³⁷, or —(CH₂)_(n)SR³⁷, wherein each n is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is selected from the group consisting of H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl and optionally substituted C₃-C₁₀cycloalkyl.

In another embodiment of the present invention, each R³⁸ isindependently halo, C₁-C₆alkyl or —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In another embodiment of the present invention, each R³⁸ isindependently —(CH₂)_(j)NR³⁹ (CH₂)_(n)R³⁶, wherein j is 1 and n is 2.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(j)NH(CH₂)A⁴R³⁷.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(j)NH(CH₂)_(n)OR³⁷, wherein j is 1 or 2 and n is 2.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)NH(CH₂)₂OR³⁷, wherein R³⁷ is optionally substituted C₁-C₆ alkyl,for example —CH₃.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)NH(CH₂)₃OR³⁷, wherein R³⁷ is optionally substituted C₁-C₆ alkyl,for example —CH₃.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₂NH(CH₂)₂OR³⁷ wherein R³⁷ is optionally substituted C₁-C₆ alkyl,for example —CH₃.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₂NH(CH₂)₃OR³⁷, wherein R³⁷ is optionally substituted C₁-C₆ alkyl,for example —CH₃.

In another embodiment of the present invention, each R³⁸ isindependently —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl), for example—(CH₂)NH(CH₂)₂S(O)₂CH₃.

In another embodiment of the present invention, each R³⁸ isindependently —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In another embodiment of the present invention, each R³⁸ isindependently —C(O)NR³⁹(CH₂)₂OR³⁷.

In another embodiment of the present invention, each R³⁸ isindependently —C(O)NH(CH₂)₂OR³⁷, wherein R³⁷ is optionally substitutedC₁-C₆ alkyl, for example —CH₃.

In another embodiment of the present invention, each R³⁸ isindependently —C(O)O—(CH₂)_(n)NR³⁶R³⁹.

In another embodiment of the present invention, each R³⁸ isindependently —C(O)O—(CH₂)_(n)NR³⁶R³⁹, wherein R³⁶ and R³⁹ are eachindependently C₁-C₆ alkyl, for example —CH₃.

In another embodiment of the present invention, each R³⁸ isindependently —C(O)O—(CH₂)_(n)NHR³⁶R³⁹, wherein R³⁶ and R³⁹ are eachindependently C₁-C₆ alkyl, for example —CH₃, and n is for example 2.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(j)NR³⁹(CH₂)_(n)C₃-C₇cycloalkyl, for example—(CH₂)NHC₃cycloalkyl.

In another embodiment of the present invention each R³⁸ is independentlyselected from the group consisting of —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein X¹ is for example Oor S.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₃P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(n)P(═O)(C₁-C₃alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₃P(═O)(C₁-C₃alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(n)P(═O)(CH₃)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₃P(═O)(CH₃)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)_(j)NHCH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₂NR³⁹(CH₂)₁₋₃P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₂NH(CH₂)₁₋₃P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₂NR³⁹(CH₂)₁₋₃P(═O)(C₁-C₃alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₂NH(CH₂)₁₋₃P(═O)(C₁-C₃alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁₋₂NH(CH₂)₁₋₃P(═O)(CH₃)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁NR³⁹(CH₂)₂P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁NH(CH₂)₂P(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁NH(CH₂)₂P(═O)(C₁-C₃alkyl)₂.

In another embodiment of the present invention each R³⁸ is independently—(CH₂)₁NH(CH₂)₂P(═O)(CH₃)₂.

In another embodiment of the present invention each R³⁸ is independentlyselected from the group consisting of—NR¹³C(O)NR¹³-arylP(═O)(C₁-C₆alkyl)₂,—NR¹³C(S)NR¹³-arylP(═O)(C₁-C₆alkyl)₂,—NR¹³C(O)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(S)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂.

In another embodiment of the present invention each R³⁸ is independentlyselected from the group consisting of—NR¹³C(O)NR¹³-arylP(═O)(C₁-C₃alkyl)₂,—NR¹³C(S)NR¹³-arylP(═O)(C₁-C₃alkyl)₂,—NR¹³C(O)NR¹³-heteroarylP(═O)(C₁-C₃alkyl)₂ and—NR¹³C(S)NR¹³-heteroarylP(═O)(C₁-C₃alkyl)₂.

In another embodiment of the present invention, each R³⁸ isindependently selected from—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, wherein R⁹⁹ isselected from NH₂ and —NR³R⁴.

In another embodiment of the present invention, each R³⁸ isindependently selected from—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, wherein R⁹⁹ is NH₂.

In another embodiment of the present invention, each R³⁸ isindependently selected from—(CH₂)_(j)NH(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, wherein R⁹⁹ is NH₂.

In another embodiment of the present invention, each R³⁸ isindependently selected from —(CH₂)₁NH(CH₂)₂₋₃[O(CH₂)₂]₂₋₃(CH₂)₀₋₁R⁹⁹,wherein R⁹⁹ is NH₂.

In another embodiment of the present invention, each R³⁸ isindependently selected from —(CH₂)₁NH(CH₂)₃[O(CH₂)₂]₃(CH₂)₁R⁹⁹ and—(CH₂)₁NH(CH₂)₂[O(CH₂)₂]₂R⁹⁹, wherein R⁹⁹ is NH₂.

In another embodiment of the present invention, R³⁸ is—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein the —(CH₂)_(n)— group is optionallysubstituted with C₁-C₆alkyl, for example Me, R³⁶ is —(CH₂)_(n3)A⁴R³⁷,for example —(CH₂)_(n3)OR³⁷ wherein each n3 is an integer independentlyranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is —C(O)—C₁-C₃alkyl, for example—C(O)—CH₃.

In another embodiment of the present invention, D is substituted with anR³⁸ as described an embodiment herein, and further substituted with haloor C₁-C₆alkyl.

In another embodiment of the present invention, D is phenyl orpyridinyl, and R³⁸ is C₁-C₆alkyl,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ or—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein X¹ is for example Oor S.

In another embodiment of the present invention, R³⁹ is H or C₁-C₆alkyl.

In another embodiment of the present invention, R³⁹ is H.

In another embodiment of the present invention, D is a 5- or 6-memberedaryl or a 5- or 6-membered heteroaryl, optionally substituted with oneor two (alternatively one) R³⁸, wherein each said R³⁸ is independentlyselected from the group consisting of halo, C₁-C₆ alkyl, —C(O)NR³⁶R³⁹,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ and —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, whereineach j is an integer independently selected from 0 to 4 (alternatively 1to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), iis 2 or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀aryl), —(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, forexample —(CH₂)_(n3)OR³⁷ or —(CH₂)_(n3)SR³⁷, wherein each n3 is anindependently selected integer ranging from 0 to 6 (alternatively 0 to4, alternatively 0 to 2, alternatively 1 or 0, alternatively 0), and R³⁷is H or C₁-C₆alkyl, for example, C₁-C₆alkyl, alternatively C₁-C₂alkyl.

According to another embodiment of the present invention, D is phenyl orpryidinyl (alternatively pyridinyl), optionally substituted with one ortwo (alternatively one) R³⁸, wherein each said R³⁸ is independentlyselected from the group consisting of halo, C₁-C₆ alkyl, —C(O)NR³⁶R³⁹,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ and —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, whereineach j is an integer independently selected from 0 to 4 (alternatively 1to 4, alternatively 1 or 2, alternatively 1), n is an integer from 0 to6 (alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), iis 2 or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀aryl), —(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, forexample —(CH₂)_(n3)OR³⁷ or —(CH₂)_(n3)SR³⁷, wherein n3 is an integerranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), and R³⁷ is H or C₁-C₆alkyl, forexample, C₁-C₆alkyl, alternatively C₁-C₂alkyl.

In another embodiment of the present invention, D is a 5- or 6-memberedaryl or a 5- or 6-membered heteroaryl, optionally substituted with oneor two (alternatively one) R³⁸, wherein each said R³⁸ is independentlyselected from the group consisting of halo, C₁-C₆ alkyl,—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein X¹ is for example Oor S, j is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2 to6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl,and R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example, C₁-C₆alkyl,alternatively C₁-C₂alkyl.

According to another embodiment of the present invention, D is phenyl orpryidinyl (for example, pyridinyl), optionally substituted with one ortwo (for example, one) R³⁸, wherein each said R³⁸ is independentlyselected from group consisting of halo, C₁-C₆ alkyl,—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heleroarylP(═O)(C₁-C₆alkyl)₂, wherein X¹ is for example Oor S, wherein j is an integer from 0 to 4 (alternatively 1 to 4,alternatively 1 or 2, alternatively 1), n is an integer from 0 to 6(alternatively 2 to 6, alternatively 2 to 4, alternatively, 1 or 2), R³⁹is H or C₁-C₆alkyl, and R³⁶ is selected from the group consisting of H,—OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),—(CH₂)_(n)(5-10 membered heterocyclyl) and —(CH₂)_(n)A⁴R³⁷, for example,—(CH₂)_(n)OR³⁷ or —(CH₂)_(n)SR³⁷, wherein each n is an independentlyselected integer ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), and R³⁷ isH or C₁-C₆alkyl, for example, C₁-C₆alkyl, alternatively C₁-C₂alkyl.

According to another embodiment of the present invention, A⁴ is O.

In another embodiment of the present invention, M is a structureselected from the group consisting of

-   wherein-   * represents the point of attachment to D;-   † represents the point of attachment to Z;-   A¹ is selected from the group consisting of —CH₂—, —O—, —S—, —N(H)—,    —N(C₁-C₆ alkyl)-, —N—(Y-aryl)-, —N-OMe, —NCH₂OMe and N-Bn;-   Y is a bond or —(C(R^(x))(H))_(t)—, wherein t is an integer from 1    to 6; and-   R^(x) at each occurrence is independently selected from the group    consisting of H and C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is    optionally substituted;-   A² is selected from the group consisting of N and CR, wherein R is    selected from the group consisting of —H, halogen, —CN, C₁-C₆ alkyl,    C₂-C₆ alkenyl, C₂-C₆ alkynyl, —COOH and —C(O)Oalkyl, wherein the    C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and —C(O)Oalkyl are    optionally substituted;-   each A³ is independently selected from the group consisting of CH,    C-D and N, for example, CH or N;-   each R⁸⁰ is independently selected from the group consisting of H,    halogen, NO₂, cyano, OR⁸³, N(R⁸³)₂, CO₂R⁸³, C(O)N(R⁸³)₂, SO₂R⁸³,    SO₂N(R⁸³)₂, NR⁸³SO₂R⁸³, NR⁸³C(O)R⁸³, NR⁸³CO₂R⁸³, —CO(CH₂)₁R⁸³,    —CONH(CH₂)₁R⁸³, alkylaminoalkyl, alkylaminoalkynyl, C₁-C₆alkyl,    substituted C₁-C₆alkyl, C₃-C₇cycloalkyl, substituted    C₃-C₇cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted    alkynyl, hydroxyalkyl, aryl, substituted aryl, heteroaryl,    substituted heteroaryl, arylalkyl, substituted arylalkyl,    heterocycloalkyl, and substituted heterocycloalkyl; and-   each R⁸³ is independently selected from the group consisting of H,    alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,    substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,    substituted heteroaryl, heterocycloalkyl, and substituted    heterocycloalkyl; or-   two R⁸³ taken together with the N atom to which they are attached    form a heterocyclic ring.    In another embodiment of the present invention, M is a structure    selected from the group consisting of

-   wherein-   J is CR⁸⁰ or N;-   R⁸² is selected from the group consisting of H, C₁-C₆alkyl or    substituted C₁-C₆alkyl, —Y-(aryl), —Y-(heteroaryl), -alkoxy and    —CH₂OMe;-   wherein *, †, R⁸⁰ and Y are as defined above.

In another embodiment of the present invention, M is a structureselected from the group consisting of

-   wherein-   † is as defined above; and-   R²² is selected from the group consisting of —H, —C₁-C₆alkyl,    —Y-aryl, alkoxy, —CH₂—O-Me and —Bn.

According to another embodiment of the present invention, M is

In another embodiment of the present invention, A¹ is S.

In another embodiment of the present invention, A² is —CH— or —C(CN)—.

In another embodiment of the present invention, A³ is —C(R^(q))— or N,wherein R^(q) is selected from the group consisting of H, halogen, NO₂,cyano, OR^(r), NR^(r)R^(r), CO₂R^(r), C(O)NR^(r)R^(r), SO₂R^(r),SO₂NR^(r)R^(r), NR^(r)SO₂R^(r), NR^(r)C(O)R^(r), NR^(r)CO₂R^(r),—CO(CH₂)₀₋₄R^(r), —CONH(CH₂)₀₋₄R^(r), alkylaminoalkyl,alkylaminoalkynyl, C₁-C₆alkyl, substituted C₁-C₆alkyl, C₃-C₇cycloalkyl,substituted C₃-C₇cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, hydroxyalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, arylalkyl, substituted arylalkyl,heterocycloalkyl and substituted heterocycloalkyl; wherein each R^(r) isindependently selected from the group consisting of H, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heterocycloalkyl and substituted heterocycloalkyl.

According to another embodiment of the present invention, Z is selectedfrom the group consisting of —O—, —S— and —NR⁵—, wherein R⁵ is selectedfrom the group consisting of H, an optionally substituted (C₁-C₅)acyland C₁-C₆ alkyl-O—C(O), wherein C₁-C₆ alkyl is optionally substituted.

According to another embodiment of the present invention, Z is —O—.

According to another embodiment of the present invention, Ar is a6-membered aromatic or heteroaromatic ring system.

According to another embodiment of the present invention, Ar is a6-membered aromatic ring system.

According to another embodiment of the present invention, Ar is selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, wherein each of said phenyl, pyrazine, pyridazine,pryimidine and pyridine is optionally substituted with 0 to 4 R² groups.

According to another embodiment of the present invention, Ar is phenyl,optionally substituted with 0 to 4 R² groups, for example, with betweenzero and four halo.

In another embodiment of the present invention, G is B-L-T.

In another embodiment of the present invention G is

In another embodiment of the present invention G is selected from thegroup consisting of

In another embodiment of the compounds according to the presentinvention, G is selected from the group consisting of

-   wherein R¹³, R¹⁴, Q, R⁶⁰ and R³ are as defined above;-   any methylene group is independently optionally substituted with    R²⁵, wherein-   R²⁵ is selected from the group consisting of halogen, trihalomethyl,    —CN, —NO₂, —NH₂, —OR³, —NR³, R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³,    —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, an    optionally substituted aryl, an optionally substituted arylalkyl, an    optionally substituted heteroarylalkyl, and an optionally    substituted (C₁-C₆)alkyl, or-   two R²⁵, together with the carbon or carbons to which they are    attached, can combine to form a three- to seven-membered alicyclic    or heteroalicyclic, or-   two R²⁵, on a single carbon can be oxo;-   R⁹ is selected from the group consisting of a C₁₋₆ alkyl on which    one or more hydrogen atoms are optionally substituted by —R²⁴,    -T¹-R¹⁵, or —NR¹⁶R¹⁷, a —N(R¹⁸)(R¹⁹) moiety and a saturated or    unsaturated three- to eight-membered carbocyclic or heterocyclic    group which is optionally substituted by a C₁₋₆ alkyl, a C₁₋₆    alkoxy, a halogen atom, nitro, a trifluoromethyl, a C₁₋₆ alkoxy    carbonyl, cyano, a cyano C₁₋₆ alkyl, a C₁₋₆ alkylthio, a phenoxy, an    acetyl, or a saturated or unsaturated five- or six-membered    heterocyclyl ring wherein, when the three- to eight-membered    carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl    groups, the two alkyl groups may combine together to form an    alkylene chain, or the three- to eight-membered carbocyclic or    heterocyclic group may be a bicyclic group condensed with another    saturated or unsaturated three- to eight-membered carbocyclic or    heterocyclic group,-   wherein-   T¹ is selected from the group consisting of —O—, —S— and —NH—;-   R²⁴ represents a saturated or unsaturated three- to eight-membered    carbocyclic or heterocyclic group;-   R¹⁵, R¹⁶, and R¹⁷, which may be the same or different, represent a    C₁₋₆ alkyl or a saturated or unsaturated three- to eight-membered    carbocyclic or heterocyclic group; wherein the three- to    eight-membered carbocyclic or heterocyclic group represented by R²⁴,    R¹⁵, R¹⁶, and R¹⁷ is optionally substituted by a C₁₋₆ alkyl, a C₁₋₆    alkoxy, a halogen atom, nitro, a trifluoromethyl, a C₁₋₆ alkoxy    carbonyl, a cyano, a cyano C₁₋₆ alkyl, a C₁₋₆ alkylthio, a phenoxy,    an acetyl, or a saturated or unsaturated five- or six-membered    heterocyclyl ring; and wherein when the three- to eight-membered    carbocyclic or heterocyclic group is substituted by two C₁₋₆ alkyl    groups, the two alkyl groups may combine together to form an    alkylene chain; and wherein the three- to eight-membered carbocyclic    or heterocyclic group may be a bicyclic group condensed with another    saturated or unsaturated three- to eight-membered carbocyclic or    heterocyclic group; and-   R¹⁸ and R¹⁹, which may be the same or different, represent (1) a    hydrogen atom, (2) a C₁₋₆ alkyl which is optionally substituted by a    C₁₋₆ alkoxy, a C₁₋₆ alkylthio, or a saturated or unsaturated three-    to eight-membered carbocyclic or heterocyclic group in which the    three- to eight-membered carbocyclic or heterocyclic group is    optionally substituted by a C₁₋₆ alkyl, a C₁₋₆ alkoxy, a halogen    atom, nitro, a trifluoromethyl, a C₁₋₆ alkoxy carbonyl, cyano, a    cyano C₁₋₆ alkyl, a C₁₋₆ alkylthio, a phenoxy, an acetyl, or a    saturated or unsaturated five- or six-membered heterocyclyl ring and    wherein when the three- to eight-membered carbocyclic or    heterocyclic group is substituted by two C₁₋₆ alkyl groups, the two    alkyl groups may combine together to form an alkylene chain, or the    three- to eight-membered carbocyclic or heterocyclic group may be a    bicyclic group condensed with another saturated or unsaturated    three- to eight-membered carbocyclic or heterocyclic group, or (3) a    saturated or unsaturated three- to eight-membered carbocyclic or    heterocyclic group which is optionally substituted by a C₁₋₆ alkyl,    a C₁₋₆ alkoxy, a halogen atom, nitro, a trifluoromethyl, a C₁₋₆    alkoxy carbonyl, cyano, a cyano C₁₋₆ alkyl, a C₁₋₆ alkylthio, a    phenoxy, an acetyl, or a saturated or unsaturated five- or    six-membered heterocyclyl ring and in which, when the three to    eight-membered carbocyclic or heterocyclic group is substituted by    two C₁₋₆ alkyl groups, the two alkyl groups may combine together to    form an alkylene chain, or the three- to eight-membered carbocyclic    or heterocyclic group may be a bicyclic group condensed with another    saturated or unsaturated three- to eight-membered carbocyclic or    heterocyclic group;-   X³ and X⁴ are each independently selected from the group consisting    of —H, halogen, cyano, nitro, C₁-C₆ alkyl, or-   X³ and X⁴ together with the atom to which they are attached form a    C₃-C₄ cycloalkyl;-   each E³ is independently selected from the group consisting of —O—,    —N(R¹³)—, —CH₂— and —S(O)₀₋₂;-   J² is selected from the group consisting of —O—, —N(R¹³)—, —CH₂— and    —C(═O)N(R¹³);-   J³ represents —C(R²⁶)(R²⁷)—, wherein-   R²⁶ and R²⁷ are independently selected from the group consisting of    a hydrogen atom, a C₁₋₄ alkyl, a C₁₋₄ alkoxy and —N(R^(12b)),    wherein-   R^(12b) is a hydrogen atom or a C₁₋₄ alkyl;-   each V is independently selected from the group consisting of ═N—    and ═C(H)—;-   R²¹ and R²³ are independently selected from the group consisting of    H, halogen, —OH, unsubstituted —O—(C₁-C₆alkyl), substituted    —O—(C₁-C₆alkyl), unsubstituted —O-(cycloalkyl), substituted    —O-(cycloalkyl), unsubstituted —NH(C₁-C₆alkyl), substituted    —NH(C₁-C₆alkyl), —NH₂, —SH, unsubstituted —S—(C₁-C₆alkyl),    substituted —S—(C₁-C₆alkyl), unsubstituted C₁-C₆alkyl and    substituted C₁-C₆alkyl; or-   R²¹ and R²³ taken together with the atom to which they are attached    form a C₃-C₇ ring system, wherein said ring system is optionally    substituted;-   d is 0, 1, 2 or 3;-   e is 0, 1, 2 or 3; and-   f is 0 or 1.

According to another embodiment of the present invention, G is selectedfrom the group consisting of

In another embodiment of the present invention, G is selected from thegroup consisting of

-   wherein each methylene in any of the above formulae, other than    those in a depicted ring, is independently optionally substituted    with R²⁵;-   R^(5a) is —H or an optionally substituted (C₁-C₆)alkyl;-   R¹⁰ is an azolyl, wherein one or more hydrogen atoms are optionally    substituted by a moiety selected from the group consisting of a    halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, trihalomethyl,    nitro, amino optionally independently substituted by one or two of    C₁₋₄ alkyl, a C₁₋₄ alkoxycarbonyl C₁₋₄ alkyl, a C₁₋₄ alkylcarbonyl    and a C₃₋₅ cyclic alkyl.

In another embodiment of the compounds according to the presentinvention, a methylene group between two carbonyl groups is mono- ordi-substituted with either an optionally substituted (C₁-C₆)alkyl or anoptionally substituted spirocycle.

In another embodiment of the compounds according to the presentinvention, R¹⁰ is selected from the group consisting of

-   wherein A⁸ is selected from the group consisting of —O—, —S— and    —NH—; and-   R^(22a) and R^(23a) are independently selected from the group    consisting of —H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio,    trihalomethyl, nitro, amino optionally independently substituted by    one or two of C₁₋₄ alkyl, a C₁₋₄ alkoxycarbonyl C₁₋₄ alkyl, a C₁₋₄    alkylcarbonyl and a C₃₋₅ cyclic alkyl.

According to another embodiment of the present invention, G is selectedfrom the group consisting of

According to another embodiment of the present invention, G is selectedfrom the group consisting of

According to another embodiment of the present invention, G is selectedfrom the group consisting of

According to another embodiment of the present invention, G is selectedfrom the group consisting of

According to another embodiment of the present invention, G is selectedfrom the group consisting of

According to another embodiment of the present invention, G is selectedfrom the group consisting of

According to another embodiment of the present invention, any of E, E¹,E² or E³ are independently —NH—.

According to another embodiment of the present invention, one of R^(18a)and R^(19a) is —CF₃ and the other is —H.

According to another embodiment of the present invention, R¹¹ and R¹²are each —H.

According to another embodiment of the present invention, X is S or O,for example, S.

According to another embodiment of the present invention, R¹³ is H.

According to another embodiment of the present invention, R¹¹, R¹² andR¹³ are each —H.

According to another embodiment of the present invention, X is O, one ofR^(18a) and R^(19a) is —CF₃ and the other is —H, and R¹¹, R¹² and R¹³are each —H.

According to another embodiment of the present invention, W is selectedfrom the group consisting of

wherein P¹ is a five- to seven-membered ring, including the two sharedcarbon atoms of the aromatic ring to which P¹ is fused, and wherein P¹optionally contains between one and three heteroatoms.

According to another embodiment of the present invention, W is selectedfrom the group consisting of phenyl, napthyl,1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl,pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl,isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; eachoptionally substituted.

According to another embodiment of the present invention, W is selectedfrom the group consisting of phenyl, napthyl,1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl,pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl,isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; eachoptionally substituted with one or more of R14a, R15a, R16a and R17a.

According to another embodiment of the present invention, W is phenyl,optionally substituted.

According to another embodiment of the present invention, W is phenyl,optionally substituted with one or more of R^(14a), R^(15a), R^(16a) andR^(17a).

According to another embodiment of the present invention, W issubstituted by a halogen and either an alkenyl or alkynyl.

According to another embodiment of the present invention W is phenylsubstituted by a halogen and either an alkenyl or alkynyl.

In another embodiment of the compounds according to the presentinvention, Q is selected from the group consisting of

wherein P¹ is a five- to seven-membered ring, including the two sharedcarbon atoms of the aromatic ring to which P¹ is fused, and wherein P¹optionally contains between one and three heteroatoms.

In another embodiment of the compounds according to the presentinvention, Q is selected from the group consisting of phenyl, napthyl,1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl,pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl,isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzoxazolyl, furyl, thienyl, benzothieliyl, and oxadiazolyl; eachoptionally substituted with between one and four of R²⁰, wherein

According to another embodiment of the present invention, Q is phenyl,optionally substituted.

According to another embodiment of the present invention, Q is phenyl,optionally substituted with one or more of R²⁰.

According to another embodiment of the presention invention, Q issubstituted by a halogen and either an alkenyl or alkynyl.

According to another embodiment of the presention invention Q is phenylsubstituted by a halogen and either an alkenyl or alkynyl.

According to another embodiment of the present invention, R^(14a) andR^(15a) are both H, R^(16a) is C₂-C₇ alkenyl or C₂-C₆ alkynyl andR^(17a) is halogen, for example fluorine.

In another embodiment, L³ and L⁴ are independently —CH— or N.

In another embodiment of the present invention, R³⁹ is selected from thegroup consisting of H, C₁-C₆alkyl and C₁-C₆cycloalkyl

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —C(O)NR³⁶R³⁹, —C(O)O—(CH₂)_(n)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl), —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ and —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ (for example—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶) wherein each j is an integer independentlyselected from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), i is 2 or 3, R³⁹ is H orC₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10membered heterocyclyl) and —(CH₂)_(n)A⁴R³⁷, for example —(CH₂)_(n)OR³⁷or —(CH₂)_(n)SR³⁷, wherein each n is an independently selected integerranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), and R³⁷ is H or C₁-C₆alkyl, forexample, C₁-C₆alkyl, alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group;

M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments each R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —C(O)NR³⁶R³⁹, —C(O)O—(CH₂)_(n)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆alkyl), —(CH₂)_(j)NR³⁹ (CH₂)_(n)R³⁶and —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, (for example—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶) wherein each j is an integer independentlyselected from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), i is 2 or 3, R³⁹ is H orC₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl),—(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, forexample, —(CH₂)_(n3)OR³⁷ or —(CH₂)_(n3)SR³⁷, wherein n3 is an integerranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), and R³⁷ is H or C₁-C₆alkyl, forexample, C₁-C₆alkyl, alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —C(O)NR³⁶R³⁹, —C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl), —(CH₂)_(j)NR³⁹ (CH₂)_(n)R³⁶ and—C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, (for example —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶)wherein each j is an integer independently selected from 0 to 4(alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is aninteger from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4,alternatively, 1 or 2), i is 2 or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group;

M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —C(O)NR³⁶R³⁹, —C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl), —(CH₂)_(j)NR³⁹ (CH₂)_(n)R³⁶ and—C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, (for example,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶) wherein each j is an integer independentlyselected from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), i is 2 or 3, R³⁹ is H orC₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl),—(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, forexample, —(CH₂)_(n3)OR³⁷ or —(CH₂)_(n3)SR³⁷, wherein n3 is an integerranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), and R³⁷ is H or C₁-C₆alkyl, forexample, C₁-C₆alkyl, alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein said phenyl groups of G are optionally substituted with from 0to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰,wherein each R²⁰ is selected from, for example, halogen, trihalomethyl,alkoxy, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl. In someembodiments, R²⁰ is halogen. In some embodiments, Ar is phenyloptionally substituted with 0 to 4 R² groups, for example with betweenzero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —C(O)NR³⁶R³⁹, —C(O)O—(CH₂)_(n)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆alkyl), —(CH₂)_(j)NR³⁹ (CH₂)_(n)R³⁶and —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, (for example,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶) wherein each j is an integer independentlyselected from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), i is 2 or 3, R³⁹ is H orC₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl),—(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, forexample, —(CH₂)_(n3)OR³⁷ or —(CH₂)_(n3)SR³⁷, wherein n3 is an integerranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), and R³⁷ is H or C₁-C₆alkyl, forexample C₁-C₆alkyl, alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein said phenyl groups of G are optionally substituted with from 0to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰,wherein each R²⁰ is selected from, for example, for example halogen,trihalomethyl, alkoxy, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl. In someembodiments, R²⁰ is halogen. In some embodiments, Ar is phenyloptionally substituted with 0 to 4 R² groups, for example with betweenzero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridyl (for example, pyridyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group;

M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein said phenyl groups of G are optionally substituted with from 0to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰,wherein each R²⁰ is selected from, for example, for example halogen,trihalomethyl, alkoxy, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl. In someembodiments, R²⁰ is halogen. In some embodiments, Ar is phenyloptionally substituted with 0 to 4 R² groups, for example with betweenzero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridyl (for example, pyridyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —C(O)NR³⁶R³⁹, —C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆alkyl), —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ and—C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, (for example,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶) wherein each j is an integer independentlyselected from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), i is 2 or 3, R³⁹ is H orC₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl),—(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, forexample, —(CH₂)_(n3)OR³⁷ or —(CH₂)_(n3)SR³⁷, wherein n3 is an integerranging from 0 to 6 (preferably 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), and R³⁷ is H or C₁-C₆alkyl, forexample, C₁-C₆alkyl, alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein said phenyl groups of G are optionally substituted with from 0to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰wherein each R²⁰ is selected from, for example, halogen, trihalomethyl,alkoxy, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl. In someembodiments, R²⁰ is halogen. In some embodiments, Ar is phenyloptionally substituted with 0 to 4 R² groups, for example with betweenzero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ (for example—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂), wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example, —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example, C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example, pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ (for example,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂), wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example, —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example, C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, for example halogen, trihalomethyl, alkoxy,optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenylor optionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ (for example,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂), wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example, —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example, C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; and

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example, pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ (for example,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂), wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example, —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example. C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein Q is optionally substituted with from 0 to 4 (alternatively 0 to2, alternatively 1) independently selected R²⁰, wherein each R²⁰ isselected from, for example, halogen, trihalomethyl, alkoxy, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl oroptionally substituted C₂-C₆alkynyl. In some embodiments, R²⁰ ishalogen. In some embodiments, Ar is phenyl optionally substituted with 0to 4 R² groups, for example with between zero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 to 5 independently selected R³⁸groups, alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ (for example,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂), wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example, —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example, C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein said phenyl groups of G are optionally substituted with from 0to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰,wherein each R²⁰ is selected from, for example, halogen, trihalomethyl,alkoxy, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl. In someembodiments, R²⁰ is halogen. In some embodiments, Ar is phenyloptionally substituted with 0 to 4 R² groups, for example with betweenzero and four halo.

In another embodiment of the present invention,

D is phenyl or pyridinyl (for example, pyridinyl), each of which isoptionally substituted with 1 to 5 independently selected R³⁸ groups,alternatively 1 to 3 independently selected R³⁸ groups, andalternatively 1 or 2 independently selected R³⁸ group, wherein each saidR³⁸ is independently selected from the group consisting of halo, C₁-C₆alkyl, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂ (for example,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂), wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), R³⁹ is H or C₁-C₆alkyl, and R³⁶ isselected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, for example, —(CH₂)_(n3)OR³⁷ or—(CH₂)_(n3)SR³⁷, wherein n3 is an integer ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), and R³⁷ is H or C₁-C₆alkyl, for example, C₁-C₆alkyl,alternatively C₁-C₂alkyl;M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—, forexample, —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, for example selectedfrom the group consisting of phenyl, pyrazine, pyridazine, pryimidineand pyridine, each of which is optionally substituted with 0 to 4 R²groups, for example with between zero and four halo; andG is

wherein said phenyl groups of G are optionally substituted with from 0to 4 (alternatively 0 to 2, alternatively 1) independently selected R²⁰,wherein each R²⁰ is selected from, for example, halogen, trihalomethyl,alkoxy, optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl or optionally substituted C₂-C₆alkynyl. In someembodiments, R²⁰ is halogen. In some embodiments, Ar is phenyloptionally substituted with 0 to 4 R² groups, for example with betweenzero and four halo.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 or 2 independently selected R³⁸groups;

M is

Z is —O—, —S—, —SO—, —SO₂—, —CH₂O—, —OCH₂—, —CH₂— or —N(R⁵)—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 or 2 independently selected R³⁸groups;

M is

Z is —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl, each ofwhich is optionally substituted with 1 or 2 independently selected R³⁸groups, wherein R³⁸ is C₁-C₆alkyl or —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, whereinj is an integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), and the —(CH₂)_(n)— groupis optionally substituted with C₁-C₆alkyl (for example Me), R³⁶ is—(CH₂)_(n3)A⁴R³⁷, for example —(CH₂)_(n3)OR³⁷, wherein each n3 is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H or—C(O)—C₁-C₃alkyl (for example, —C(O)—CH₃);M is

Z is —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is imidazolyl, pyridinyl or phenyl, each of which is optionallysubstituted with 1 or 2 independently selected R³⁸ groups, wherein R³⁸is C₁-C₆alkyl or —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integerfrom 0 to 4 (alternatively 1 to 4, alternatively 1 or 2, alternatively1), n is an integer from 0 to 6 (alternatively 2 to 6, alternatively 2to 4, alternatively, 1 or 2), and the —(CH₂)_(n)— group is optionallysubstituted with C₁-C₆alkyl, for example Me, R³⁶ is —(CH₂)_(n3)A⁴R³⁷,for example —(CH₂)_(n3)OR³⁷ wherein each n3 is an integer independentlyranging from 0 to 6 (alternatively 0 to 4, alternatively 0 to 2,alternatively 1 or 0, alternatively 0), wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H or —C(O)—C₁-C₃alkyl (for example,—C(O)—CH₃);M is

Z is —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is imidazolyl substituted with C₁-C₆alkyl (for example Me) and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4(alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is aninteger from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4,alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷ wherein each n3 is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H;M is

Z is —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is imidazolyl substituted on a nitrogen atom with C₁-C₆alkyl (forexample Me) and on a carbon atom with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,wherein j is an integer from 0 to 4 (alternatively 1 to 4, alternatively1 or 2, alternatively 1), n is an integer from 0 to 6 (alternatively 2to 6, alternatively 2 to 4, alternatively, 1 or 2), and R³⁶ is—(CH₂)_(n3)OR³⁷ wherein each n3 is an integer independently ranging from0 to 6 (alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or0, alternatively 0), wherein the R³⁷ is optionally substituted C₁-C₆alkyl, and R³⁹ is H;M is

Z is —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is imidazolyl substituted with C₁-C₆alkyl (for example Me) and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4(alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is aninteger from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4,alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷ wherein each n3 is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is imidazolyl substituted with C₁-C₆alkyl (for example Me) and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4(alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is aninteger from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4,alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷ wherein each n3 is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;G is

whereinR¹³ is H; andQ is optionally substituted with from 0 to 4 independently selected R²⁰.

In another embodiment of the present invention,

D is imidazolyl substituted with C₁-C₆alkyl (for example Me) and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4(alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is aninteger from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4,alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷ wherein each n3 is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;G is

whereinR¹³ is H;X³ and X⁴ are each H or taken together with the carbon to which they areattach are cyclopropyl; andQ is cycloalkyl, heteroaryl or phenyl, optionally substituted with from0 to 4 independently selected R²⁰.

In another embodiment of the present invention,

D is imidazolyl substituted with C₁-C₆alkyl (for example Me) and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4(alternatively 1 to 4, alternatively 1 or 2, alternatively 1), n is aninteger from 0 to 6 (alternatively 2 to 6, alternatively 2 to 4,alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷ wherein each n3 is aninteger independently ranging from 0 to 6 (alternatively 0 to 4,alternatively 0 to 2, alternatively 1 or 0, alternatively 0), whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl (for example Me), and R³⁹is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;G is

whereinR¹³ is H;X³ and X⁴ are each H or taken together with the carbon to which they areattach are cyclopropyl; andQ is cyclopropyl, isoxazole or phenyl, optionally substituted with from0 to 2 independently selected R²⁰, for example halogen (for example F),C₁-C₆alkyl or —CF₃.

In another embodiment of the present invention,

D is pyridinyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j isan integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷wherein each n3 is an integer independently ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), wherein the R³⁷ is optionally substituted C₁-C₆ alkyl,and R³⁹ is H;M is

Z is —O—;Ar is a 6-membered aryl or 6-membered heteroaryl, each of which isoptionally substituted with 0 to 4 R² groups; andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is pyridinyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ wherein j isan integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷wherein each n3 is an integer independently ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), wherein the R³⁷ is optionally substituted C₁-C₆ alkyl,and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;andG is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In another embodiment of the present invention,

D is pyridinyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j isan integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷wherein each n3 is an integer independently ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), wherein the R³⁷ is optionally substituted C₁-C₆ alkyl,and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;G is

for example,

whereinR¹³ is H; andQ is optionally substituted with from 0 to 4 independently selected R²⁰.

In another embodiment of the present invention,

D is pyridinyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j isan integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷wherein each n3 is an integer independently ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), wherein the R³⁷ is optionally substituted C₁-C₆ alkyl,and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;G is

for example,

whereinR¹³ is H;X³ and X⁴ are each H or taken together with the carbon to which they areattach are cyclopropyl; andQ is cycloalkyl, heteroaryl or phenyl, optionally substituted with from0 to 4 independently selected R²⁰.

In another embodiment of the present invention,

D is pyridinyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j isan integer from 0 to 4 (alternatively 1 to 4, alternatively 1 or 2,alternatively 1), n is an integer from 0 to 6 (alternatively 2 to 6,alternatively 2 to 4, alternatively, 1 or 2), and R³⁶ is —(CH₂)_(n3)OR³⁷wherein each n3 is an integer independently ranging from 0 to 6(alternatively 0 to 4, alternatively 0 to 2, alternatively 1 or 0,alternatively 0), wherein the R³⁷ is optionally substituted C₁-C₆ alkyl(preferably Me), and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen, for example, one F;G is

for example,

whereinR¹³ is H or C₁-C₆ alkyl;X³ and X⁴ are each H or taken together with the carbon to which they areattach are cyclopropyl; andQ is cyclopropyl, cyclopentyl, cyclohexyl, pyridine or phenyl,optionally substituted with from 0 to 2 independently selected R²⁰, forexample halogen (for example F), C₁-C₆alkyl, —S(O)₂(C₁-C₆)alkyl,—C(O)NH₂, —C(O)(C₁-C₆)alkyl or —CF₃.

In another embodiment of the present invention,

D is tetrahydropyridine substituted with —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,wherein j is an integer from 0 to 4, n is an integer from 0 to 6, andR³⁶ is —(CH₂)_(n3)OR³⁷ wherein n3 is an integer ranging from 0 to 6,wherein the R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen; andG is

Q is cycloalkyl, heteroaryl or phenyl (for example cyclopropyl, phenylor isoxazole), optionally substituted with from 0 to 4 independentlyselected R²⁰ (for example halogen, —CF₃ or —C₁-C₆alkyl).

In another embodiment of the present invention

D is tetrahydropyridine substituted on nitrogen with—C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4, nis an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ wherein n3 is aninteger ranging from 0 to 6, wherein the R³⁷ is optionally substitutedC₁-C₆ alkyl, and R³⁹ is H;M is

Z is —O—;Ar is phenyl substituted with at least one halogen; andG is

Q is cycloalkyl, heteroaryl or phenyl (for example cyclopropyl, phenylor isoxazole), optionally substituted with from 0 to 4 independentlyselected R²⁰ (for example halogen, —CF₃ or —C₁-C₆alkyl).

In another embodiment of the present invention,

D is phenyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is aninteger from 0 to 4, n is an integer from 0 to 6, and the —(CH₂)_(n)—group is optionally substituted with C₁-C₆alkyl, R³⁶ is —(CH₂)_(n3)OR³⁷,wherein n3 is an integer ranging from 0 to 6, the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H or —C(O)—C₁-C₃alkyl;M is

Z is —O—;Ar is phenyl substituted with at least one halogen; andG is

whereinQ is phenyl or isoxazole optionally substituted with from 0 to 4independently selected halogen or C₁-C₆alkyl;R13 is H; andX³ and X⁴ are each H or taken together with the carbon to which they areattached are cyclopropyl.

Certain compounds of above formulas may generally be prepared accordingto the following Schemes. Tautomers and solvates (e.g., hydrates) of thecompounds of above formulas are also within the scope of the presentinvention. Methods of solvation are generally known in the art.Accordingly, the compounds of the present invention may be in the free,hydrate or salt form, and may be obtained by methods exemplified by thefollowing schemes below.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It should be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto.

Examples of compounds according to the invention include those describedin the examples below. Compounds were named using Chemdraw Ultra version10.0 or version 8.0.3, which are available through Cambridgesoft.com,100 Cambridge Park Drive, Cambridge, Mass. 02140, or were derivedtherefrom.

The data presented herein demonstrate the inhibitory effects of thekinase inhibitors of the invention. These data lead one to reasonablyexpect that the compounds of the invention are useful not only forinhibition of kinase activity, protein tyrosine kinase activity, orother embodiments thereof, such as, VEGF receptor signaling and HGFreceptor signaling, but also as therapeutic agents for the treatment ofproliferative diseases, including cancer and tumor growth.

Synthetic Schemes and Experimental Procedures

The compounds of the invention can be prepared according to the reactionschemes or the examples illustrated below utilizing methods known to oneof ordinary skill in the art. These schemes serve to exemplify someprocedures that can be used to make the compounds of the invention. Oneskilled in the art will recognize that other general syntheticprocedures may be used. The compounds of the invention can be preparedfrom starting components that are commercially available. Any kind ofsubstitutions can be made to the starting components to obtain thecompounds of the invention according to procedures that are well knownto those skilled in the art.

PARTICULAR EXAMPLES

tert-Butyl(2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(46) Step 1. 5-(1,3-Dioxan-2-yl)-1-methyl-1H-imidazole (38) [Shaflee A.,Rastkary N., Jorjani M., Shafaghi B., Arch. Pharm. Pharm. Med. Chem.2002, 2, 69-76]

To a solution of 1-methyl-1H-imidazole-5-carbaldehyde (2.9 g, 26.3 mmol)in toluene (20 mL) was added propane-1,3-diol (4.01 g, 52.7 mmol) andCSA (0.306 g, 1.317 mmol) and the reaction mixture was heated to refluxwith azeotropic removal of the evolved water for 24 hours. The reactionmixture was cooled to RT, diluted with DCM and washed with NaHCO₃solution. It was then dried over Na₂SO₄, filtered and concentrated.Purification by column chromatography (80% EtOAc in Hexane to EtOAc)afforded 38 (2.53 g, 57% yield) as a yellow oil which solidified onstanding to a yellow solid. MS (m/z): 169.2 (M+H).

Step 2. 5-(1,3-Dioxan-2-yl)-2-iodo-1-methyl-1H-imidazole (39)

To a solution of 38 (295 g, 1.754 mmol) in dry THF (10 mL) at −78° C.was added n-BuLi (0.772 mL, 1.929 mmol, 2.5 M solution in hexanes) andthe reaction mixture was stirred for 20 min. Iodine (445 mg, 1.754 mmol)in THF (2 mL) was slowly added dropwise while maintaining thetemperature at −78° C. and the reaction mixture was stirred for afurther 30 min, and was quenched by the addition of water and thenextracted with EtOAc. The organic phase was, washed with sodiumthiosulfate solution, separated, dried over Na₂SO₄, filtered andconcentrated. Purification by column chromatography (20% EtOAc/Hexane)afforded 39 (305 mg, 59% yield) as a white solid. MS (m/z): 294.1 (M+H).

Step 3.2-(5-(1,3-Dioxan-2-yl)-1-methyl-1H-imidazol-2-yl)-7-chlorothieno[3,2-b]pyridine(40)

To a solution of 7-chlorothieno[3,2-b]pyridine (1) [Klemm, L. H.;Louris, J. N.; Boisvert, W.; Higgins, C.; Muchiri, D. R.; J.Heterocyclic Chem., 22, 1985, 1249-1252] (11.7 g, 69.0 mmol) in THF (300mL) was added, at −78° C., a solution of n-BuLi (30.46 mL, 76 mmol, 2.5M in hexanes) and the reaction mixture was stirred for 10 min. Asolution of ZnCl₂ (76.15 mL, 76 mmol, 1.0 M in Et₂O) was added and themixture was stirred at RT for 10 min. Pd(PPh₃)₄ (2.287 mg, 0.104 mmol)was added along with a solution of 39 (5.82 g, 19.79 mmol) in THF (20mL) and the reaction mixture was heated to reflux under an atmosphere ofN₂ gas for 4 hours. The reaction was then cooled to RT, and diluted withammonium hydroxide and EtOAc. The organic phase was collected, driedover Na₂SO₄, filtered and concentrated. The resultant material wastriturated with Et₂O to afford the title compound 40 (5.79 g, 87% yield)as a white solid. MS (m/z): 336.1 (M+H).

Step 4.2-(5-(1,3-Dioxan-2-yl)-1-methyl-1H-imidazol-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine,(41)

A mixture of 40 (5.9 g, 17.57 mmol), 2-fluoro-4-nitrophenol (5.52 g,35.1 mmol) and NaHCO₃ (1.346 g, 16.02 mmol) in Ph₂O (7 mL) was heated to180° C. for 4 hours. The reaction mixture was cooled to RT and dilutedwith DCM, filtered and concentrated. Purification of the residue bycolumn chromatography (eluent EtOAc) afforded 41 (2.5 g, 31% yield) as ayellow solid. MS (m/z): 457.1 (M+H).

Step 5.2-(5-(Dimethoxymethyl)-1-methyl-1H-imidazol-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(42)

To a solution of 41 (2.5 g, 5.48 mmol) in MeOH (200 mL) was added CSA(127 mg, 0.548 mmol) and the reaction mixture was heated to reflux for 5hours. It was then cooled to RT and solid NaHCO₃ was added. The mixturewas filtered and the filtrate was concentrated to dryness. The residualsolid was dissolved in DCM, washed with water, dried over Na₂SO₄,filtered and concentrated. The resultant solid was triturated with Et₂Oto afford 42 (1.8 g, 74% yield) which was used without any furtherpurification. MS (m/z): 445.1 (M+H).

Step 6.2-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carbaldehyde(43)

To a solution 42 (1.8 g, 4.05 mmol) in acetone (100 mL) and water (100mL) was added diluted HCl (20 mL, 2M, 40.0 mmol) and the reactionmixture was stirred at RT overnight. It was then concentrated todryness. The residual solid was dissolved in DCM, washed with water,dried over Na₂SO₄, filtered and concentrated. The resultant solid wastriturated with Et₂O to afford 43 (1.3 g, 81% yield), which used withoutadditional purification. MS (m/z): 399.2 (M+H).

Step 7.N-((2-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)-2-methoxyethanamine(44)

To a suspension of 43 (1.3 g, 3.26 mmol) in dry DCM (50 mL) at RT wasadded 2-methoxyethanamine (1.226 g, 16.32 mmol), acetic acid (0.98 g,16.32 mmol) and sodium triacetoxyborohydride (3.46 g, 16.32 mmol), andthe reaction mixture was stirred at RT for 24 hours. It was then dilutedwith additional DCM and washed with saturated NaHCO₃ solution, driedover Na₂SO₄, filtered and concentrated to dryness to afford 44 (1.5 g,100% yield) as an yellow oil which was used crude in the next step withno additional purification. MS (m/z): 458.2 (M+H).

Step 8. tert-Butyl(2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(45)

To a solution of 44 (1.5 g, 3.28 mmol) in DCM (50 mL) at RT was addedBoc₂O (1.073 mg, 4.92 mmol) and the reaction mixture was stirred at RTovernight. The mixture was concentrated to dryness and the residue waspurified by column chromatography (eluent EtOAc) to afford 45 (1.3 g,71% yield) as a yellow solid. MS (m/z): 558.2 (M+H).

Step 9. tert-Butyl(2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(46)

To a solution of 45 (1.1 g, 0.717 mmol) in MeOH (30 mL) and water (10mL) was added ammonium chloride (211 mg, 3.95 mmol) and zinc (1.61 g,17.76 mmol) and the reaction mixture was heated to reflux for 24 hours.The reaction mixture was cooled to RT then concentrated to dryness. Theresidue was partitioned between DCM and water and the organic phase wascollected, dried over Na₂SO₄, filtered and concentrated to afford thetitle compound 46 (1.04 g, 100% yield), which was used crude in the nextstep with no additional purification. MS (m/z): 528.1 (M+H).

Example 12N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(48) Step 10. tert-Butyl(2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(47)

To a solution of 46 (375 mg, 0.711 mmol) in a mixture of EtOH (5 mL) andtoluene (5 mL) at RT was added phenylacetyl isothiocyanate (189 mg,1.066 mmol) and the reaction mixture was stirred at RT for 3 hours. Themixture was concentrated to dryness then purified by columnchromatography (eluent a gradient of 80% EtOAc in hexane to EtOAc), toafford 47 (400 mg, 80%) as a red solid. MS (m/z): 705.2 (M+H).

Step 11.N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(48)

To a solution of 47 (400 mg, 0.568 mmol) in toluene (10 mL) was addedTFA (0.874 mL, 11.35 mmol) and the reaction mixture was stirred at RTovernight. The mixture was concentrated to dryness and the residue waspurified by Gilson Reverse Phase HPLC (Aquasil C₁₈, elient a lineargradient of 35% MeOH in water to 95% MeOH in water with 0.05% of formicacid, 60 min run) to afford 48 as a white solid, (305 mg, 65% yield) asthe TFA salt. MS (m/z): 605.3 (M+H).

Example 13N¹-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-phenylmalonamide(49) Step 1. tert-Butyl(2-(7-(2-fluoro-4-(3-oxo-3-(phenylamino)propanamido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(47a)

To a solution of 46 (333 mg, 0.631 mmol) in DMF (8 mL) at RT was added3-oxo-3-(phenylamino)propanoic acid (226 mg, 2 eq, 1.262 mmol) and EDC(242 mg, 2 eq, 1.262 mmol), and the reaction mixture was stirred at RTfor 24 hours. It was then concentrated to dryness then purified bycolumn chromatography (eluent a gradient of 80% EtOAc in hexane toEtOAc), to afford 47a (357 mg, 82% yield) as a white solid. MS (m/z):689.4 (M+H).

Step 2.N¹-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-phenylmalonamide(49)

To a solution of 47 (357 mg, 0.518 mmol) in toluene (20 mL) was addedTFA (0.799 mL, 20 eq, 10.36 mmol) and the reaction mixture was stirredat RT for 5 hours. The mixture was concentrated to dryness and theresidue was purified by Gilson Reverse Phase HPLC (Aquasil C₁₈, elient alinear gradient of 35% MeOH in water to 95% MeOH in water with 0.05% offormic acid, 60 min run) to afford 49 as a yellow solid (270 mg, 88%yield) as the TFA salt. Characterization of compound 49 is provided inthe Table 1.

Example 14N¹-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-methyl-N3-phenylmalonamide(50)

Title compound 50 was obtained similarly to the compound 49 startingfrom the compound 46 (scheme 2) and using3-(methyl(phenyl)amino)-3-oxopropanoic acid [US 2007/0004675 A-1]instead of 3-oxo-3-(phenylamino)propanoic) acid. Characterization of 50is provided in the Table 1.

Example 15N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(51)

Title compound 51 was obtained similarly to the compound 49 startingfrom the compound 46 (scheme 2) and using1-(phenylcarbamoyl)cyclopropanecarboxylic acid [US 2007/0004675 A-1]instead of 3-oxo-3-(phenylamino)propanoic) acid. Characterization of 51is provided in the Table 1.

Example 16N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamide(52)

Title compound 52 was obtained similarly to the compound 49 startingfrom the compound 46 (scheme 2) and using2-oxo-3-phenylimidazolidine-1-carbonyl chloride [US 2007/0004675 A-1] inthe presence of Hunig's base in DCM instead of3-oxo-3-(phenylamino)propanoic) acid. Characterization of 52 is providedin the Table 1.

TABLE 1 Cpd. # Ex. # Structure Characterization 49 13

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.60 (s, 1 H), 10.22 (s, 1 H), 8.95(s, 2 H), 8.56 (d, J = 5.28 Hz, 1 H), 8.12 (s, 1 H), 7.90 (m, 1 H), 7.60(m, 2 H), 7.49 (m, 3 H), 7.31 (m, 3 H), 7.05 (m, 1 H), 6.74 (m, 1 H),4.35 (m, 1 H), 3.93 (s, 3 H), 3.60 (m, 2 H), 3.51 (s, 2 H), 3.31 (s, 3H), 3.21 (m, 2 H). LCMS: 589.3 (M + H). (mono-formate salt) MS (m/z):589.3 (M + H). 50 14

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.29 (s, 1 H), 8.50 (m, 1 H), 8.49(m, 1 H), 8.17 (s, 2 H), 7.90 (m, 2 H), 7.76 (m, 1 H), 7.46 (m, 10 H),3.91 (s, 1 H), 3.90 (s, 3 H), 3.77 (m, 2 H), 3.38 (m, 4 H), 2.71 (m, 4H), (mono-formate salt). MS (m/z): 603.3 (M + H). 51 15

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.46 (s, 1 H), 10.01 (s, 1 H), 9.5(s, 2 H), 8.70 (m, 1 H), 8.15 (m, 1 H), 7.92 (m, 1 H), 7.62 (m, 2 H),7.51 (m, 3 H), 7.31 (m, 3 H), 7.05 (m, 1 H), 6.98 (m, 1 H), 3.98 (s, 3H), 3.36 (m, 2 H), 3.66 (m, 2 H), 3.31 (s, 3 H), 3.18 (m, 2 H), 1.47 (s,4 H) (tris-trifluoroacetate salt). MS (m/z): 615.3 (M + H). 52 16

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.51 (s, 1 H), 8.51 (m, 1 H), 8.21(s, 1 H), 7.89 (s, 1 H), 7.86 (m, 1 H), 7.61 (m, 2 H), 7.47 (m, 5 H),7.16 (t, J = 7.04, 1 H), 6.95 (s, 1 H), 6.67 (m, 1 H), 3.95 (s, 4 H),3.90 (s, 3 H), 3.75 (s, 2 H), 3.39 (m, 2 H), 3.23 (s, 3 H), 2.68 (m, 3H). (tris- trifluoroacetate salt) MS (m/z): 616.3 (M + H).

tert-Butyl2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(2-methoxyethyl)carbamate (80) Step 1.4-Bromo-1-(2-chloroethyl)-1H-pyrazole (75)

To a solution of 4-bromo-1H-pyrazole (5 g, 34.02 mmol), 2-chloroethanol(2.7 mL, 40.82 mmol) and PPh₃ (10.71 g, 40.82 mmol) and in THF (68 mL)at 0° C. was added DEAD (6.4 mL, 40.8 mmol). The mixture was allowed towarm-up to room temperature and stirred overnight. It was thenconcentrated under reduced pressure, the residue was treated with etherand the resultant suspension was filtered. The filtrate was collectedand concentrated under reduced pressure to afford the title compound 75which was used in the next step without further purification. MS (m/z).209.0 (M+H).

Step 2. 2-(4-Bromo-1H-pyrazol-1-yl)-N-(2-methoxyethyl)ethanamine (76)

A solution of 2-methoxyethanamine (8.9 mL, 102.06 mmol) and chloride 75(7.13 g, 34.02 mmol) in DMSO (20 mL) was heated at 60° C. 5 h. Themixture was then cooled to room temperature, diluted with EtOAc, washedwith aqueous sodium bicarbonate, water and brine. The organic phase wasfurther extracted with 1N HCl and the acid extract was collected andbasified with 2N NaOH (pH˜11). The basic aqueous solution was extractedwith DCM, the DCM extract was dried over anhydrous sodium sulphate, andconcentrated under reduced pressure to afford title compound 76 (8.44 g,99%) as brown foam. MS (m/z): 248.04 (M+H).

Step 3. tert-Butyl2-(4-bromo-1H-pyrazol-1-yl)ethyl(2-methoxyethyl)carbamate (77)

A solution of 76 (8.44 g, 34.02 mmol) and Boc₂O (8.91 g, 40.82 mmol) inTHF (68 mL) was stirred overnight at room temperature. The reactionmixture was transferred onto a flash chromatography column and elutedwith EtOAc/Hexane 1:3, to afford title compound 77 (4.2 g, 35%) astransparent syrup. MS (m/z): 349.08 (M+1).

Step 4. tert-Butyl2-methoxyethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate(78)

A mixture of 77 (369.3 mg, 1.06 mmol), bis(pinacolato)diboron (323.2 mg,1.27 mmol), Pd(PPh₃)₄ (61.3 mg, 0.05 mmol) and AcOK (312.3 mg, 3.18mmol) in THF (2.1 mL) was heated to reflux overnight under nitrogen. Itwas then diluted with DCM, washed with water, dried over anhydroussodium sulphate and concentrated under reduced pressure affording crude78 (11.06 mmol, 100% yield) that was used in the next step withoutfurther purification. MS (m/z): 396.2 (M+H).

Step 5: tert-Butyl2-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(2-methoxyethyl)carbamate(79)

A mixture of 78 (369.3 mg, 0.93 mmol),7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US2006/0287343 A1] (466.6 mg, 1.12 mmol), Pd(PPh₃)₄ (54 mg, 0.05 mmol) andNa₂CO₃ (305 mg, 2.8 mmol) in DME (1.9 mL) was heated to reflux overnightunder nitrogen. It was then diluted with DCM, washed with water, driedover anhydrous sodium sulphate and concentrated under reduced pressure.The residue was purified by flash chromatography, eluents EOAc/Hex 1:1,EtOAc, 5% MeOH in DCM affording title compound 79 (203 mg, 39%) as brownsyrup. MS (m/z): 558.2 (100%) (M+H).

Step 6. tert-Butyl2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(2-methoxyethyl)carbamate (80)

Starting from the nitro compound 79 and following the proceduredescribed below for the synthesis of compound 126 (Scheme 6, step 4,example 49), title compound 80 was obtained in 100% yield. MS (m/z):528.3 (100%) (M+H).

Example 24N-(3-Fluoro-4-(2-(1-(2-(2-methoxyethylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(81)

Title compound 81 was obtained similarly to the compound 48 (example 12)but starting from the amine 80 (scheme 3). Characterization of 81 isprovided in the Table 2.

Example 25N-(3-Fluoro-4-(2-(1-(2-(2-methoxyethylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(82)

Title compound 82 was obtained similarly to the compound 51 (example 15)but starting from the amine 80 (scheme 3) and using1-(4-fluorophenylcarbamoyl)cyclopropane-carboxylic acid instead of1-(phenylcarbamoyl)cyclopropanecarboxylic acid. Characterization of 82is provided in the Table 2.

Example 26N-(3-Fluoro-4-(2-(1-(2-(2-methoxyethylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(83)

Title compound 83 was obtained similarly to the compound 51 (example 15)but starting from the amine 80 (scheme 3) and using1-(phenylcarbamoyl)cyclopropanecarboxylic acid. Characterization of 83is provided in the Table 2.

Example 27N¹-(3-Fluoro-4-(2-(1-(2-(2-methoxyethylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-methyl-N³-phenylmalonamide(84)

Title compound 84 was obtained similarly to the compound 50 (example 14)but starting from the amine 80 (scheme 3) and using3-(methyl(phenyl)amino)-3-oxopropanoic acid. Characterization of 84 isprovided in the Table 2.

TABLE 2 Cpd. Ex. No. No. Structure Characterization 81 24

¹H-NMR (DMSO-D₆, 400 MHz) 12.5 (br, 1 H), 11.85 (br, 1 H), 8.48 (d, J =5.5 Hz, 1 H), 8.41 (s, 1 H), 8.11 (dd, J = 0.6 Hz, 1 H), 8.07 (d, J =12.13 Hz, 1 H), 7.75 (s, 1 H), 7.74- 7.50 (m, 2 H), 7.37-7.24 (m, 5 H),6.62 (dd, J = 5.5 Hz, J = 0.8 Hz, 1 H), 4.45 (t, J = 6.26 Hz, 2 H), 3.83(s, 2 H), 3.59-3.53 (m, 3 H), 3.36-3.33 (m, 3 H), 3.29 (s, 3 H), 3.04(t, J = 5.1 Hz, 2 H) (presumably a dihydrochloride salt). MS (m/z):605.2 (M + 1). 82 25

¹H NMR (400 MHz, MeCN-d₃) δ (ppm): 10.11 (s, 1 H), 8.85 (s, 1 H), 8.56(d, J = 6.5 Hz, 1 H), 8.32 (s, 1 H), 8.06 (s, 1 H), 7.88 (dd, J = 12.7,2.2 Hz, 1 H), 7.83 (s, 1 H), 7.56-7.53 (m, 2 H), 7.53-7.43 (m, 1 H),7.38 (m, 1 H), 7.13-7.08 (m, 2 H), 6.88 (dd, J = 6.5, 0.8 Hz, 1 H), 4.54(dd, J = 6.3, 6.0 Hz, 2 H), 3.63 (t, J = 5 Hz, 2 H), 3.55 (m, 2 H), 3.35(s, 3 H), 3.24 (m, 2 H), 1.65-1.62 (m, 4 H) (presumablybis-trifluoroacetate salt). MS (m/z): 633.2 (M + 1). 83 26

¹H NMR (400 MHz, CD₃CN) δ (ppm): 10.06 (s, 1 H), 8.86 (s, 1 H), 8.56 (d,J = 6.4 Hz, 1 H), 8.22 (s, 1 H), 8.05 (s, 1 H), 7.88 (dd, J = 12.9, 2.3Hz, 1 H), 7.82 (s, 1 H), 7.56-7.54 (m, 2 H), 7.46-7.34 (m, 4 H), 7.17-7.13 (m, 1 H), 6.87 (d, J = 6.4 Hz, 1 H), 4.54 (dd, J = 5.5, 5.1 Hz, 2H), 3.63 (dd, J = 5.3, 4.9 Hz, 2 H), 3.55 (dd, J = 5.3, 4.9 Hz, 2 H),3.35 (s, 3 H), 3.24 (dd, J = 5.3, 4.7 Hz, 2 H), 1.65-1.62 (m, 4 H) diTFA salt. MS (m/z): 615.2 (M + 1). 84 27

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1 H), 8.79 (br, 1 H), 8.51(d, J = 5.7 Hz, 1 H), 8.44 (s, 1 H), 8.18 (d, J = 0.4 Hz, 1 H), 7.82 (d,J = 11.3 Hz, 1 H), 7.78 (s, 1 H), 7.50-7.33 (m, 7 H), 6.68 (d, J = 5.7Hz, 1 H), 4.51 (dd, J = 6.3, 6.1 Hz, 2 H), 3.58 (dd, J = 5.3, 4.9 Hz, 2H), 3.48 (m, 2 H), 3.31 (s, 3 H), 3.23 (s, 2 H), 3.21 (s, 3 H), 3.18 (m,2 H) (presumably dihydrochloride salt) MS (m/z): 603.3 (M + 1).

Example 33N¹-(3-Fluoro-4-(2-(1-(3-(2-methoxyethylamino)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-methyl-N³-phenylmalonamide(102) Step 1.1-(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one(98)

Acryloyl chloride (131.3 mL, 1.62 mmol) was added to a suspension of7-(2-fluoro-4-nitrophenoxy)-2-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridine(85) [US 2007/0004675 A1] (150 mg, 0.40 mmol) and K₂CO₃ (223.4 1.62mmol) and the mixture was stirred overnight at room temperature. It wasthen filtered and concentrated under reduced pressure affording titlecompound 98 (172 mg, 100% yield) that was used in the next step withoutfurther purification. MS (m/z): 426.1 (M+1)

Step 2.1-(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(2-methoxyethylamino)propan-1-one(99)

A solution of the compound 98 (171.0 mg, 0.4 mmol) and2-methoxyethanamine (0.14 mL, 1.62 mmol) in THF (98.1 mL) was stirredovernight at room temperature. It was then diluted with DCM, washed withaqueous sodium bicarbonate and water. The organic phase was extractedwith 1N HCl, the aqueous acidic phase was basified by addition of 1NNaOH (pH 11) and extracted with DCM. The DCM extract was dried overanhydrous sodium sulphate and concentrated under reduced pressureaffording title compound 99 (89.0 mg, 45% yield) as cream foam. MS(m/z): 501.2 (M+1).

Step 3: tert-Butyl3-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-oxopropyl(2-methoxyethyl)carbamate(100)

To a solution of compound 99 (89 mg, 0.178 mmol) in THF (1.778 mL)di-tert-butyl dicarbonate (46.6 mg, 0.213 mmol) was added. The reactionmixture was stirred at room temperature overnight, poured onto a silicagel column and eluted with 5% MeOH in CH₂Cl₂, affording title compound100 (106 mg, 99% yield) as a red syrup. MS (m/z): 601.3 (M+1).

Step 4: tert-Butyl3-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-oxopropyl(2-methoxyethyl)carbamate(101)

Starting from the nitro compound 100, title compound 101 was obtained byfollowing the same procedures as described below for the synthesis ofcompound 126 (Scheme 6, step 4). MS (m/z): 571.3 (M+1).

Steps 5 and 6.N¹-(3-Fluoro-4-(2-(1-(3-(2-methoxythylamino)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-methyl-N-phenylmalonamide(102)

Title compound 102 was obtained similarly to the compound 84 (example27, Table 2)

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.72 (dd, J=6.6, 1.6 Hz, 1H), 7.87 (dd,J=12.5, 1.6 Hz, 1H), 7.68 (s, 1H), 7.52-7.36 (m, 7H), 7.12 (dd, J=6.8,1.6 Hz, 1H), 6.77-6.73 (m, 1H), 4.95-4.34 (m, 2H), 3.91 (t, J=5.7 Hz,0.9H), 3.82 (t, J=5.7 Hz, 1.1H), 3.69-3.66 (m, 2H), 3.43 (s, 3H),3.38-3.35 (m, 2H), 3.34 (s, 2H), 3.33 (s, 3H), 3.28 (m, 2H), 2.98 (t,J=6.0 Hz, 1.1H), 2.91 (t, J=6.0 Hz, 0.9H), 2.84 (m, 1.1H), 2.74 (m,0.9H) (presumably di-hydrochloride salt). MS (m/z): 646.3 (M+1).

Example 36N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)furan-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamide(110) Step 1.5-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)furan-2-carbaldehyde(107)

A stirred suspension of7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US2006/0287343 A1] (5.00 g, 12.01 mmol, scheme 4)],5-formyl-2-furanboronic acid (2.19 g, 15.19 mmol), Pd(PPh₃)₂Cl₂ (422 mg,0.6 mmol), Na₂CO₃ (8.53 g, 80.50 mmol) in a mixture of DME/ethanol/water(60 mL/40 mL/40 mL) was degassed with nitrogen for 15 min, and heated at65° C. for five hours under nitrogen. The reaction mixture was allowedto cool to room temperature, and filtered. The cake was successivelywashed with water and AcOEt. The filtrate and washings were combined,extracted with AcOEt. The extract was successively washed with water,saturated solution of ammonium chloride, water and brine, andconcentrated. The residue was combined with the cake, absorbed on silicagel and subjected to flash column chromatography on silica gel (eluentsAcOEt/DCM: 10/90 to 20/90, then MeOH/DCM: 5/95) followed by triturationwith AcOEt, to afford aldehyde 107 (3.886 g, 84% yield) as a pale claysolid. MS (m/z): 385.0 (M+H).

Step 2.N-((5-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)furan-2-yl)methyl)-2-methoxyethanamine(108)

A suspension of 107 (2.00 g, 5.20 mmol), 2-methoxyethylamine (1.954 g,26.02 mmol), NaBH(OAc)₃ (5.52 g, 26.02 mmol) and acetic acid (1.49 ml,26.02 mmol) in anhydrous dichloromethane was stirred at room temperatureunder nitrogen for five days. The reaction mixture was then carefullyquenched with a saturated solution of NaHCO₃ (pH 8-9), and extractedwith DCM. The extract was dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the title compound 108 as ayellow-orange sticky oil. The material was used in the next step withoutfurther purification. MS (m/z): 444.2 (M+H).

Steps 3 and 4. tert-Butyl(5-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)furan-2-yl)methyl(2-methoxyethyl)carbamate(109)

Title compound 109 was obtained in 2 steps from 108 as a yellow stickyfoam, following similar procedures as for the compound 45 (Scheme 1) andcompound 126 (Scheme 6). MS (m/z): 514.3 (M+H).

Steps 5 and 6.N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)furan-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamide(110)

Title compound 110 was obtained in two steps according to proceduressimilar to ones used for the synthesis of compound 52 (example 16,Table 1) as an off-white solid ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.59(s, 1H), 8.50 (d, J=5.5 Hz, 1H), 7.86 dd, J=12.9, 2.3 Hz, 1H), 7.77 (s,1H), 7.67-7.61 (m, 2H), 7.50 (t, J=8.7 Hz, 1H), 7.48-7.40 (m, 3H), 7.18(ti, J=7.4, 1.1 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 6.64 (dd, J=5.5, 1.0Hz, 1H), 6.47 (d, J=3.5 Hz, 1H), 4.02-3.91 (m, 4H), 3.78 (s, 2H), 3.40(t, S=5.7 Hz, 2H), 3.24 (s, 3H), 2.71 (t, J=5.7 Hz, 2H), 2.26-2.06 (m,1H). MS (m/z): 602.3 (M+H).

Compounds 111-113 (examples 37-39) were prepared in two steps from theamine 109 similarly to compounds 48 (scheme 2, example 12,) and 51(Table 2). Characterization of compounds 111-113 (examples 37-39) isprovided in the Table 3.

TABLE 3 111-113: Examples 37-39

Cpd. Ex. R Name Characterization 111 37

N-(3-fluoro-4-(2-(5- ((2- methoxyethylamino)- methyl)furan-2-yl)thieno[3,2- b]pyridin-7- yloxy)phenylcarba- mothioyl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.55-12.30 (m, 1 H),12.05- 11.60 (m, 1 H), 8.51 (d, J = 5.5 Hz, 1 H), 8.02 (dd, J = 12.3,1.3 Hz, 1 H), 7.77 (s, 1 H), 7.58-7.50 (m, 2 H), 7.39-7.25 (m, 5 H),7.09 (d, J = 3.1 Hz, 1 H), 6.65 (dd, J = 5.5, 0.8 Hz, 1 H), 6.47 (d, J =3.3 Hz, 1 H), 3.83 (s, 2 H), 3.78 (s, 2 H), 3.40 (t, J = 5.7 Hz, 2 H),3.24 (s, 3 H), 2.71 (t, J = 5.7 Hz, 2 H), one NH is missing. MS (m/z):591.2 (M + H). 112 38

N-(3-fluoro-4-(2-(5- ((2- methoxyethylamino)- methyl)furan-2-yl)thieno[3,2- b]pyridin-7- yloxy)phenylcarba- mothioyl)-2-(4-fluorophenyl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.56-12.38(m, 1 H), 11.94- 11.74 (m, 1 H), 8.52 (d, J = 5.5 Hz, 1 H), 8.02 (dd, J= 12.3, 1.2 Hz, 1 H), 7.77 (s, 1 H), 7.58-7.50 (m, 2 H), 7.42-7.35 (m, 2H), 7.22-7.15 (m, 2 H), 7.09 (d, J = 3.3 Hz, 1 H), 6.65 (dd, J = 5.5,0.8 Hz, 1 H), 6.47 (d, J = 3.3 Hz, 1 H), 3.83 (s, 2 H), 3.78 (s, 2 H),3.40 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.71 (t, J = 5.7 Hz, 2 H), oneNH is missing. MS (m/z): 609.2 (M + H). 113 39

N-(3-fluoro-4-(2-(5- ((2- methoxyethylamino)- methyl)furan-2-yl)thieno[3,2- b]pyridin-7- yloxy)phenyl)-N- phenylcyclopropane-1,1-dicarboxamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.38 (s, 1 H),9.99 (s, 1 H), 8.49 (d, J = 5.4 Hz, 1 H), 8.17 (s, 1 H), 7.90 (dd, J =13.2, 2.2 Hz, 1 H), 7.77 (s, 1 H), 7.63 (dd, J = 8.6, 1.2 Hz, 2 H), 7.52(dd, J = 9.1, 1.9 Hz, 1 H), 7.46 (t, J = 8.8 Hz, 1 H), 7.34- 7.27 (m, 2H), 7.12-7.04 (m, 2 H), 6.60 (d, J = 5.5 Hz, 1 H), 6.48 (d, J = 3.3 Hz,1 H), 3.79 (s, 2 H), 3.41 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.72 (t,J = 5.6 Hz, 2 H), 2.08 (s, 1 H), 1.52- 1.44 (m, 4 H). MS (m/z): 601.3(M + H).

Compounds 114-115 (examples 40-41) were prepared starting from5-bromopicolinaldehyde (Wang X., Rabbat P., O'Shea P., Tillyer R.,Grabovski E. J. J., Reider P. S., Tetrahedron Lett. 2000, 41, 4335) and7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US2006/0287343 A1] according to the synthetic procedures similar to onesshown in the Scheme 5. Characterization of compounds 114-115 (examples40-41) is provided in the Table 4.

TABLE 4 114-115: Examples 40-41

Cpd Ex. R¹ R² Name Characterization 114 40 H

N-(3-fluoro-4-(2-(6- ((2- methoxyethylamino) methyl)pyridin-3-yl)thieno[3,2- b]pyridin-7- yloxy)phenylcarba- mothioyl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆): 12.50 (bs, 1 H), 11.84 (bs, 1H), 9.09 (d, J = 2.2 Hz, 1 H), 8.55 (d, J = 5.3 Hz, 1 H), 8.31 (dd, J =8.1, 2.5 Hz, 1 H), 8.23 (s, 1 H), 8.13 (s, 1 H), 8.02 (m, 1 H), 7.59 (d,J = 8.4 Hz, 1 H), 7.55 (m, 2 H), 7.32-7.35 (m, 4 H), 7.28 (m, 1 H), 6.68(bd, J = 5.5 Hz, 1 H), 4.09 (s, 2 H), 3.82 (s, 2 H), 3.50 (m, 2 H), 3.27(s, 3 H), 2.91 (m, 2 H). MS (m/z): 602.3 (M + H). 115 41 H

N-(3-fluoro-4-(2-(6- ((2- methoxyethylamino) methyl)pyridin-3-yl)thieno[3,2- b]pyridin-7- yloxy)phenylcarba- mothioyl)-2-(4-fluorophenyl)acetamide ¹H NMR (400 MHz, DMSO-d₆): 12.47 (bs, 1 H), 11.83(bs, 1 H), 9.13 (d, J = 2.2 Hz, 1 H), 8.56 (d, J = 5.5 Hz, 1 H), 8.34(dd, J = 8.2, 2.5 Hz, 1 H), 8.26 (s, 1 H), 8.12 (s, 1 H), 7.61 (d, J =8.4 Hz, 1 H), 7.55 (m, 2 H), 7.55 (m, 2 H), 7.35- 7.39 (m, 2 H),7.15-7.20 (m, 2 H), 6.69 (bd, J = 5.5 Hz, 1 H), 4.21 (s, 2 H), 3.82 (s,2 H), 3.55 (m, 2 H), 3.29 (s, 3 H), 3.03 (m, 2 H). MS (m/z): 620.3 (M +H).

Example 49N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamide(128) Step 1.6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinaldehyde(123)

To a solution of 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine(24) [US 2006/0287343 A1] (6 g, 14.42 mmol) in dioxane (40 mL) wereadded 6-bromopyridine-3-carbaldehyde (3.22 g, 17.30 mmol), palladiumtetrakistriphenylphosphine (0.500 g, 0.433 mmol) andhexamethyldistannane (3.29 mL, 15.86 mmol). The mixture was heated at100° C. for 20 h. It was then concentrated and adsorbed on silica gel,transferred onto a silica gel column and eluted with DCM/MeOH (100/0,99/1, 98/2, 97/3) to afford title compound 123 (2.864 g, 50% yield). MS(m/z): 396.1 (M+H).

Step 2:N-((6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-2-methoxyethanamine(124)

A mixture of 123 (700 mg, 1.77 mmol) and 2-methoxyethanamine (185 □L,160 mg, 2.12 mmol) in DCM (7 mL) was stirred at room temperature for 10min. It was then treated with NaBH(OAc)₃ (526 mg, 2.48 mmol) and stirredat room temperature overnight. The reaction mixture was diluted with DCM(20 mL) and washed with saturated NaHCO₃ solution (20 mL). The organicphase was collected, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography using thegradient 4-8% MeOH/DCM to afford 124 (675 mg, 65% yield). MS (m/z):455.2 (M+H).

Step 3: tert-Butyl(6-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(125)

A solution of 124 (470 mg, 1.03 mmol) and Boc anhydride (338 mg, 1.55mmol) in THF (10 mL) was stirred at room temperature overnight. Thereaction mixture was then concentrated and the residue was purified byflash chromatography using EtOAc as the eluent, to afford 125 (443 mg,77% yield. MS (m/z): 555.2 (M+H).

Step 4: tert-Butyl(6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(126)

A solution of 125 (443 mg, 0.80 mmol) and NH₄Cl (37 mg, 0.68 mmol) in2:1 mixture of EtOH/water (10.5 mL) was treated with iron powder (380mg, 6.79 mmol) and stirred at reflux for 1 hour. The reaction mixturewas then filtered through a celite pad and concentrated to afford titlecompound 126 that was used without further purification (440 mg, 100%yield). MS (m/z): 525.2 (M+H).

Step 5. tert-Butyl(6-(7-(2-fluoro-4-(2-oxo-3-phenylimidazolidine-1-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(127)

A solution of 126 (100 mg, 0.19 mmol) and iso-Pr₂NEt (133 □L, 99 mg,0.76 mmol) in DCM (2 mL) was treated with3-oxo-3-phenylimidazoline-1-carbonyl chloride (51 mg, 0.23 mmol) at 0°C. and stirred at room temperature for 2 hrs. The reaction mixture wasthen concentrated and partitioned between EtOAc (5 mL) and NaHCO₃saturated solution (5 mL). The organic phase was collected, dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography using a gradient 0-5% MeOH in EtOAc as an eluent,to afford 127 (61 mg, 44%). MS (m/z): 713.3 (M+H).

Step 6.N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamide(128)

HCl gas was bubbled into a solution of 127 (61 mg, 0.08 mmol) in DCM.The flask was capped and the mixture was stirred at room temperature for30 min. Formed precipitate was collected by filtration and washed withDCM to afford 128 (52 mg, 84% yield), presumably as a trihydrochloridesalt. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.59 (s, 1H), 9.34 (br.s, 2H),8.75 (s, 1H), 8.62 (d, J=5.7 Hz, 1H), 8.43 (s, 1H), 8.38 (d, J=8.5 Hz,1H), 8.15 (dd, J=8.2, 2.1 Hz, 1H), 7.86 (dd, J=12.9, 2.4 Hz, 1H), 7.62(d, J=7.6 Hz, 2H), 7.4-7.6 (m, 4H), 7.17 (t, J=7.3 Hz, 1H), 6.81 (d,J=5.5 Hz, 1H), 4.25 (m, 2H), 3.95 (m, 4H), 3.62 (m, 2H), 3.29 (s, 3H),3.13 (br.s, 2H). MS (m/z): 613.3 (M+H).

4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline(139) Step 1. 6-(7-Chlorothieno[3,2-b]pyridin-2-ylmicotinaldehyde (136)

A solution of 7-chlorothieno[3,2-b]pyridine (1) (4.02 g, 23.70 mmol) inTHF (150 mL) [Klemm, L. H.; Louris, J. N.; Boisvert, W.; Higgins, C.;Muchiri, D. R.; J. Heterocyclic Chem., 22, 1985, 1249-1252] was cooledto −40° C. in an acetonitrile/dry ice bath. n-BuLi (9.95 mL, 24.88 mmol,2.5M in hexanes) was added by syringe, dropwise. The dark mixture wasstirred for 15 min. Zinc chloride (24.88 mL, 24.88 mmol, 1M in ether)was added by syringe. The mixture was warmed to 0° C. thentetrakistriphenylphosphine palladium (1.095 g, 0.948 mmol) was added.The dark mixture was stirred for 10 min and6-bromopyridine-3-carbaldehyde (4.41 g, 23.70 mmol) was added. Themixture was heated to reflux and a precipitate formed rapidly. After 3h, the reaction mixture was cooled down to r.t., quenched with 2 mLNH₄Cl and left overnight. The solid was isolated by suction filtration,rinsed with small amount of THF and suspended in a mixture of water (200mL) and EtOAc (100 mL), isolated by suction filtration and finallytriturated with acetic acid (100 mL) and dried in vacuum to afford titlecompound 136 (4.95 g, 76% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):10.13 (s, 1H), 9.14 (d, J=1.4 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.65 (s,1H), 8.53 (d, J=8.4 Hz, 1H), 8.39 (dd, J=8.4, 2.1 Hz, 1H), 7.65 (d,J=4.9 Hz, 1H). MS (m/z): 275.1 (M+H).

Step 1.2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)-7-chlorothieno[3,2-b]pyridine(137)

A suspension of 136 (2.69 g, 9.79 mmol), ethylene glycol (2.184 mL, 39.2mmol), and (1R)-(−)-10-camphorsulfonic acid (0.227 g, 0.979 mmol) intoluene (150 mL) was heated to reflux with a Dean-Stark trap. After 3 h,the mixture was cooled down and filtered through celite (while stillwarm). The filtrate was washed with water, NaHCO₃ (aq., sat.), NaOH (aq)and brine. The solution was then dried over MgSO₄ and concentrated toafford compound 137 (2.77 g, 89% yield) as an off-white solid. MS (m/z):319.1 (M+H).

Step 3:2-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(138)

Following the procedure described above for the synthesis of compound 41(scheme 1) but substituting compound 40 for compound 137, title compound138 was obtained in 72% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.68(d, J=1.8 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.49 (dd, J=10.4, 2.5 Hz,1H), 8.47 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23-8.21 (m, 1H), 8.00 (dd,J=8.2, 2.0 Hz, 1H), 7.73 (t, J=8.5 Hz, 1H), 6.99 (d, J=5.5 Hz, 1H), 5.89(s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H). MS (m/z): 440.1 (M+H).

Step 4:4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline(139)

Following the procedure described above for the synthesis of compound126 (Scheme 6) but substituting compound 125 for compound 138, titlecompound 139 was obtained in 95% yield. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.68 (d, J=1.8 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.36 (s, 1H),8.29 (d, J=8.2 Hz, 1H), 7.96 (dd, J=8.2, 2.0 Hz, 1H), 7.11 (t, J=9.0 Hz,1H), 6.60 (d, J=5.3 Hz, 1H), 6.53 (dd, J=13.1, 2.5 Hz, 1H), 6.44 (dd,J=8.7, 1.9 Hz, 1H), 5.87 (s, 1H), 5.55 (s, 2H), 4.11-4.07 (m, 2H),4.00-3.97 (m, 2H). MS (m/z): 410.2 (M+H).

Example 51N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(142) Step 1.N-(4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide(140)

To aniline 139 (Scheme 7) (0.46 g, 1.1 mmol) in dry DMF (20 mL) wasadded acid 1-(phenylcarbamoyl)cyclopropanecarbpxylic acid (0.46 g, 2.2mmol), DIPEA (0.98 mL, 5.6 mmol) and HATU (1.07 g, 2.81 mmol) and themixture was stirred at r.t. for 18 h. It was then partitioned betweenethyl acetate and water; the organic phase was collected, washed withwater, 1M NaOH, saturated NH₄Cl, and brine, dried (MgSO₄), filtered andconcentrated. Silica gel chromatography of the residue (eluent 2%methanol/ethyl acetate) afforded 140 (0.23 g, 34% yield). ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1H), 9.98 (s, 1H), 8.68 (s, 1H), 8.53(d, J=5.3 Hz, 1H), 8.40 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.97 (dd,J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.0 Hz, 1H), 7.62 (d, J=7.6, 2H),7.53-7.46 (m, 2H), 7.30 (t, J=7.4 Hz, 2H), 7.06 (t, J=7.4 Hz, 1H), 6.66(d, J=5.3 Hz, 1H), 5.88 (s, 1H), 4.11-3.97 (m, 4H), 1.47 (br s, 4H). MS(m/z): 597.2 (M+H).

Step 2.N-(3-Fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(141)

Compound 140 (0.22 g, 0.37 mmol) was dissolved in acetone (50 mL) togive a colorless solution. The reaction mixture was diluted with water(20 mL) and TFA (2 mL), and heated to reflux for 2 h. It was then cooledand concentrated. The precipitated product was isolated by suctionfiltration. A small amount of toluene (5 mL) was added to the wet solid,and the mixture was concentrated to remove water azeotropically. Theresidue was dried in vacuum to provide aldehyde 141 (0.21 g, 103%yield). MS (m/z): 553.2 (M+H).

Step 3:N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(142)

Aldehyde 141 (0.20 g, 0.362 mmol) and 2-methoxyethylamine (0.158 mL,1.810 mmol) were dissolved in THF (50 mL) to give a colorless solution.Sodium trisacetoxyborohydride (0.384 g, 1.810 mmol) was added and themixture was stirred at r.t. for 20 h. Additional 2-methoxyethylamine(0.158 mL, 1.810 mmol) and sodium trisacetoxyborohydride (0.384 g, 1.810mmol) were added, and the mixture was stirred for a further 20 h. It wasthen concentrated, partitioned between water and dichloromethane.Organic phase was collected, washed with H₂O, 1M NaOH, and brine, dried(MgSO₄), filtered and concentrated. The residue was purified by GilsonReverse Phase HPLC (Aquasil C₁₈, 40-90% MeOH/water, 30 min, elutes 20min) and lyophilized, to afford title compound 142. Starting material(50 mg) was also isolated.

The recovered starting material was re-subjected to the reactionconditions except in acetic acid (5 mL), with 1 mL methoxyethylamine and0.030 g sodium trisacetoxyborohydride. After stirring for 5 min themixture was concentrated. The residue was purified by Gilson ReversePhase HPLC as before. The isolated product—title compound 142 wascombined with that above (0.13 g, 59% yield) as a colorless solid. ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 10.38 (s, 1H), 9.99 (s, 1H), 8.55 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=9.4 Hz, 1H),7.92-7.87 (m, 2H), 7.62 (d, J=7.5 Hz, 2H), 7.52-7.43 (m, 2H), 7.34-7.27(m, 2H), 7.08-7.04 (m, 1H), 6.64 (d, J=5.5, 2H), 3.77 (s, 2H), 3.40 (t,J=5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J=5.7 Hz, 2H), 1.47 (s, 4H). MS(m/z): 612.3 (M+H).

Step 1. N-((6-Bromopyridin-3-yl)methyl)-2-methoxyethanamine (143)

To a solution of 6-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in DCM(40 mL). was added 2-methoxyethylamine (2.80 mL, 32.3 mmol). After 10min, sodium triacetoxyborohydride (7.98 g, 37.6 mmol) was added to themixture and it was stirred at r.t for 17 h. DCM (100 mL water (50 mL andNH₄Cl (50 mL) were added to the reaction mixture. The organic phase wascollected and the aqueous layer was extracted with DCM (3×100 mL). Thecombined organic solutions were washed with brine and concentrated underreduce pressure. The residue was purified by flash columnchromatography, eluent 98/2 to 95/5 DCM/MeOH, to afford title 143 (2.958g, 45% yield) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.31(dd, J=2.6, 0.6 Hz, 1H), 7.70 (dd, J=8.2, 2.6 Hz, 1H), 7.58 (d, J=8.4Hz, 1H), 3.69 (s, 2H), 3.37 (t, J=5.8 Hz, 2H), 3.22 (s, 3H), 2.60 (t,J=5.8 Hz, 2H). MS (m/z): 245.1 (M+H).

Step 2. tert-Butyl(6-bromopyridin-3-yl)methyl(2-methoxyethyl)carbamate(144)

To a solution of 143 (13.072 g, 53.3 mmol) in THF (40 mL) was addeddi-tert-butyl dicarbonate (14.86 mL, 64.0 mmol). The mixture was stirredat r.t. for 16 h and concentrated under reduce pressure. The residue waspurified by flash column chromatography, eluent Hexane/EtOAc:7/3, 6/4,5/5, to afford title compound 144 (16.196 g, 88% yield) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.26 (dd, J=2.4, 0.8 Hz, 1H),7.64-7.58 (m, 2H), 4.39 (s, 2H), 3.40-3.33 (m, 4H), 3.20 (s, 3H),1.41-1.31 (m, 9H). MS (m/z): 345.2 (M+H).

Step 3. tert-Butyl(6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(145)

To a solution of 7-chlorothieno[3,2-b]pyridine (1) (8.84 g, 52.1 mmol)in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether)was added at −78° C. and the reaction mixture was warmed to r.t. After 1h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and 144 (6g, 17.38 mmol) in THF (25 mL) were added and the mixture was heated toreflux for 1 h. It was then partitioned between saturated aqueous NaHCO₃solution and EtOAc. The organic layer was collected and the aqueouslayer was extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine and evaporated under reduce pressure. The residuewas purified by flash column chromatography, eluents Hexane/EtOAc:5/5,3/7, 0/10, to afford compound 145 (5.41 g, 72% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39(s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d,J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33(m, 9H). MS (m/z): 434.2 (M+H).

Step 4. tert-Butyl(6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(126)

To a solution of 4-amino-2-fluorophenol (1.933 g, 15.21 mmol) in DMSO(30 mL) was added potassium tert-butoxide (2.017 g, 17.97 mmol). After30 min, chloride 145 (6 g, 13.83 mmol) was added and the reactionmixture was heated at 100° C. for 45 min. The mixture was cooled downthen poured in water (250 mL) at 40-45° C. and stirred for 30 min. Theprecipitate was collected by filtration, washed with water (2×30 mL) anddried overnight. The crude solid was triturated with Et₂O (50 mL) for 1h, to afford title compound 126 (4.18 g, 58% yield) as a brown solid. MS(m/z): 525.2 (M+H).

Step 5. tert-Butyl(6-(7-(4-amino-3-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(126a)

To a solution of 4-amino-3-fluorophenol in DMSO (12 mL) was addedpotassium tert-butoxide (0.824 g, 7.34 mmol). After 30 min, intermediate145 (2.451 g, 5.65 mmol) was added and the reaction mixture was heatedat 100° C. for 1.5 h. It was then cooled down, poured in water (50 mL)at 40-45° C. and stirred for 30 min. EtOAc (40 mL), DCM (40 mL) andwater (40 ml) were added and pH was adjusted to 7 by addition of HCl.Solids were removed by filtration through a paper filter and the twophases were separated. The organic layer was collected, dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column chromatography, eluent DCM/MeOH:99/1, 98/2, 95/5, to affordintermediate 126a (0.952 g, 32% yield). MS (m/z): 525.2 (M+H).

Example 52N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideStep 1: tert-Butyl(6-(7-(2-Fluoro-4-(1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(146)

To aniline 126 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol)in dry DMF (20 mL) was added1-(4-fluorophenylcarbamoyl)cyclopropanecarbpxylic acid (0.35 g, 1.5mmol) and HATU (0.72 g, 1.9 mmol) and the mixture was stirred at r.t.for 18 h. It was then partitioned between ethyl acetate and water, theorganic phase was washed with water, 1M NaOH, brine, dried (MgSO₄),filtered, and concentrated. Silica gel chromatography (ethyl acetate)afforded title compound 146 (0.60 g, 74% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33(s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J=8.2, 2.1 Hz,1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.65(d, J=5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H),1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).

Step 2.N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(147)

To the compound 146 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) wasadded TFA (3 mL). The solution was stirred for 18 h then concentrated.The residue was partitioned between dichloromethane and 1M NaOH, andfiltered to remove insolubles. The organic phase was collected, washedwith 1M NaOH, brine, dried (MgSO₄), filtered, and concentrated to affordtitle compound 147 (0.35 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.51 (d,J=5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.92-7.87 (m, 2H),7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J=5.5Hz, 1H), 3.77 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t,J=5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).

Example 531-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)ureaStep 1. tert-Butyl(6-(7-(2-fluoro-4-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)-thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(148)

To a solution of triphosgene (1.00 g, 3.4 mmol) in dichloromethane (50mL) at 0° C. was added 3-methyl-5-aminoisoxazole (1.0 g, 10.2 mmol). Themixture was warmed to r.t. and stirred for 1 h. DIPEA (3.6 mL, 20.4mmol) was added to afford a carbamyl chloride suspension. Half of thissuspension was added to a solution of aniline 126 (0.26 g, 0.50 mmol) insmall portions. The mixture was heated to reflux for 2 h, then cooled.It was then washed with water, 1M NaOH, and brine, dried (MgSO₄),filtered and concentrated. Silica gel chromatography (5% methanol/ethylacetate) of the residue provided 148 (0.28 g, 87% yield). MS (m/z):649.2 (M+H).

Step 2:1-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea(149)

To compound 148 (0.27 g, 0.42 mmol) in dichloromethane (75 mL) was addedTFA (3 mL). The solution was stirred for 18 h then concentrated. Theresidue was partitioned between dichloromethane and 1M NaOH, andfiltered to remove insolubles. The organic phase was collected, washedwith 1M NaOH, brine, dried (anhydrous MgSO₄), Filtered, andconcentrated. The residue was triturated with ether to afford titlecompound 149 (0.10 g, 45% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):9.67 (s, 1H), 9.23 (s, 1H), 8.56 (d, J=1.4 Hz, 1H), 8.51 (d, J=5.3 Hz,1H), 8.31 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H),7.73 (dd, J=12.9, 2.3 Hz, 1H), 7.46 (t, J=9.0 Hz, 1H), 7.29-7.26 (m,1H), 6.65 (d, J=5.5 Hz, 1H), 6.55 (s, 1H), 3.77 (s, 2H), 3.40 (t, J=5.7Hz, 2H), 3.23 (s, 3H), 2.64 (t, J=5.7 Hz, 2H), 2.36 (s, 3H). MS (m/z):549.1 (M+H).

tert-Butyl3-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenethyl(2-methoxyethyl)carbamate(156) Step 1: 2-(3-Iodophenyl)-N-(2-methoxyethyl)acetamide (151)

To a solution of 3 iodophenylacetic acid (1.12 g, 4.3 mmol) indichloromethane (50 mL) was added oxalyl chloride (0.75 mL, 8.6 mmol)and DMF (0.05 mL). The mixture was stirred for 1 h at room temperatureand concentrated. The residue was dissolved in dry THF (40 mL) and2-methoxyethylamine (2.0 mL, 23 mmol) was added. The mixture was stirredfor 2 h and concentrated. The residue was partitioned between water andethyl acetate, the organic phase was collected, washed with 1M HCl,water, saturated NaHCO₃, brine, dried (MgSO₄), filtered and concentratedto afford pure 151 (1.23 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ (ppm):7.64-7.61 (m, 2H), 7.26-7.24 (m, 1H), 7.10-7.06 (m, 1H), 5.81 (br s,1H), 3.49 (s, 2H), 3.44-3.40 (m, 4H), 3.32 (s, 1H). MS (m/z): 320.1(M+H).

Steps 2 and 3. tert-Butyl 3-iodophenethyl(2-methoxyethyl)carbamate,(153)

To TiCl₄ (1M in dichloromethane, 7.5 mL, 7.5 mmol) at r.t. was addedsodium borohydride (0.60 g, 15 mmol) resulting in a dark blue solution.This was added to a solution of amide 151 (1.22 g, 3.8 mmol) in DME (70mL) and the resulting dark mixture was stirred for 20 h. The mixture wasconcentrated, the residue partitioned between dichloromethane andNH₄OH(aq), and filtered. The filtrate was separated, the organic phasewas washed with brine, dried (MgSO₄), filtered and concentrated toafford crude amine 152. This material was dissolved in dichloromethane(100 mL), and Boc₂O (1.06 g, 4.8 mmol), DMAP (0.055 g, 0.63 mmol) andtriethylamine (0.80 mL, 5.6 mmol) were added, and the mixture wasstirred at r.t. for 3 h. It was then washed with water, saturatedNaHCO₃, brine, dried (MgSO₄), filtered and concentrated. Silica gelchromatography (15% ethyl acetate/hexanes) provided title compound 153(0.95 g, 79% yield). MS (m/z): 305.9 (M−Boc+H).

Step 4. tert-Butyl2-methoxyethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamate(154)

Compound 153 (0.95 g, 2.3 mmol), bis(pinacolato)diboron (0.65 g, 2.6mmol), potassium acetate (0.80 g, 8.2 mmol) andtetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) were suspendedin toluene (75 mL). The mixture was degassed with an N₂ flow and heatedunder reflux for 3 h. The mixture was then cooled and the toluene wasremoved under reduced pressure. The residue was partitioned betweenwater and ethyl acetate, the organic phase was collected, washed withbrine and dried (MgSO₄), filtered, and concentrated to afford titlecompound 154, which was used in the next step with no additionalpurification.

Step 5. tert-Butyl3-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenethyl(2-methoxyethyl)carbamate(155)

Iodothienopyridine 24 (scheme 4) (0.89 g, 2.1 mmol) and boronate 154(2.3 mmol) were dissolved in dry DME (100 mL). Cesium fluoride (0.96 g,6.3 mmol) and sodium bicarbonate (0.60 g, 7.1 mmol) were dissolved inwater (5 ml each) and added to the reaction mixture.Tetrakis(triphenylphosphine)palladium (0.10 g, 0.086 mmol) was added,and the mixture was then heated to reflux for 18 h, and cooled. Themixture was partitioned between ethyl acetate and water, washed withbrine, dried (MgSO₄), filtered, and concentrated. Silica gelchromatography (25-75% ethyl acetate/hexanes) provided title compound155 (0.44 g, 37% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.60 (d,J=5.3 Hz, 1H), 8.47 (dd, J=10.6, 2.7 Hz, 1H), 8.22-8.18 (m, 1H),8.10-8.06 (m, 1H), 7.75-7.67 (m, 3H), 7.43 (t, J=7.8 Hz, 1H), 7.29-7.25(m, 1H), 6.94 (d, J=5.3 Hz, 1H), 3.45-3.25 (m, 6H), 3.23 (s, 3H), 2.83(t, J=7.2 Hz, 2H), 1.35-1.25 (m, 9H). MS (m/z): 568.3 (M+H).

Step 6. tert-Butyl3-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenethyl(2-methoxyethyl)carbamate(156)

To nitro compound 155 (0.44 g, 0.78 mmol) and zinc dust (0.65 g, 10mmol) in methanol (50 mL) was added ammonium chloride (0.075 g, 1.4mmol) in water (6 mL). The resulting mixture was heated to reflux for 2h, then cooled, filtered through celite and concentrated. Silica gelchromatography (70% ethyl acetate/hexanes) afforded title compound 156(0.36 g, 88% yield). MS (m/z): 538.3 (M+H).

Example 55N-(3-Fluoro-4-(2-(3-(2-(2-methoxyethylamino)ethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide(157) Steps 1 and 2.N-(3-Fluoro-4-(2-(3-(2-(2-methoxyethylamino)ethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide(157)

To a solution of 156 (0.17 g, 0.32 mmol) in 1:1 absolute ethanol/toluene(20 mL), p-fluorophenylacetyl isothiocyanate (0.11 g, 0.56 mmol) in 1:1absolute ethanol/toluene (5 mL) was added and the reaction was allowedto stir for 2 h at r.t. The solvents were removed under reduced pressureand the residue was purified by chromatography on silica gel (75%EtOAc/hexane) to give the intermediate Boc-protected product [not shownin the scheme] as a white solid. This material was dissolved indichloromethane (20 mL) and trifluoroacetic acid (3 mL) and stirred for6 h at r.t. The mixture was then concentrated and the residue waspurified by Gilson reverse phase HPLC (Aquasil C-18 column, 35-85%MeOH/H₂O+HCO₂H, 30 min. linear gradient elution) and lyophilized toafford title compound 157(0.100 g, 50% yield). ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 8.55 (d, J=5.3 Hz, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 8.03-8.00(m, 1H), 7.76 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.57-7.53 (m, 2H), 7.43(t, J=7.6 Hz, 1H), 7.40-7.35 (m, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.21-7.16(m, 2H), 6.67 (d, J=5.5 Hz, 1H), 3.84 (s, 2H), 3.43 (t, J=5.5 Hz, 2H),3.24 (s, 3H), 2.92-2.82 (m, 4H), 2.79 (t, J=5.5 Hz, 2H) (presumably as aformate salt). MS (m/z): 633.2 (M+H).

Example 56N-(3-Fluoro-4-(2-(3-(2-(2-methoxyethylamino)ethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamidem(159) Step 1. tert-Butyl3-(7-(2-Fluoro-4-(1-(phenylcarbamoyl)cyclopropanecarboxamido)phenoxy)-thieno[3,2-b]pyridin-2-yl)phenethyl(2-methoxyethyl)carbamate(158)

To aniline 156 (0.17 g, 0.32 mmol) in dry DMF (6 mL) was added1-(phenylcarbamoyl)cyclopropanecarbpxylic acid (0.22 g, 1.1 mmol), DIPEA(0.3 mL, 0.2 g, 1.5 mmol), and HATU (0.50 g, 1.3 mmol) and the mixturewas stirred at r.t. for 18 h. It was then partitioned between ethylacetate and water, the organic phase was collected, washed with water,NaHCO₃ (aq), brine, dried (MgSO₄), filtered, and concentrated. Silicagel chromatography (75% ethyl acetate/hexanes) provided title compound158 (0.14 g, 62% yield). MS (m/z): 725.3 (M+H).

Step 2.N-(3-Fluoro-4-(2-(3-(2-(2-methoxyethylamino)ethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(159)

Compound 158 (0.14 g, 0.20 mmol) was dissolved in dichloromethane (20mL) and trifluoroacetic acid (2 mL) and stirred for 6 h at r.t. Themixture was concentrated, purified by reverse phase HPLC (Aquasil C-18column, 35-85% MeOH/H₂O+HCO₂H, 30 min. linear gradient elution) andlyophilized to afford title compound 159 (0.080 g, 65% yield). ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1H), 9.98 (s, 1H), 8.50 (d, J=5.3Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.90 (d, J=12.9 Hz, 1H), 7.76-7.74(m, 1H), 7.72-7.68 (m, 1H), 7.63-7.60 (m, 2H), 7.53-7.39 (m, 3H),7.32-7.27 (m, 3H), 7.08-7.03 (m, 1H), 6.59 (d, J=5.5 Hz, 1H), 3.38 (t,J=5.7 Hz, 2H), 3.22 (s, 3H); 2.84-2.78 (m, 4H); 2.72 (t, J=5.7 Hz, 2H);1.48-1.46 (m, 4H) (presumably as a formate salt). MS (m/z): 625.3 (M+H).

Cpd. Ex. # # Structure Characterization 166 59

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.56 (s, 1 H), 11.75 (s, 1 H), 8.97(s, 2 H), 8.54 (d, J = 5.5, 1 H), 8.14 (s, 1 H), 8.04 (m, 1 H), 7.99 (d,J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.55 (m, 2 H), 7.22 (m, 2H), 6.98 (d, J = 8.0 Hz, 1 H), 6.90 (m, 1 H), 6.69 (d, J = 5.5 Hz, 1 H),4.2 (m, 2 H), 3.70-3.60 (m, 4 H), 3.59 (m, 2 H), 3.30 (s, 3 H), 3.11 (m,2 H) (presumably bis- trifluoroacelate salt). MS (m/z): 631.2 (M + H).167 60

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.6 (s, 1 H), 9.61 (s, 1 H), 8.90 (s,2 H), 8.52 (m, 1 H), 8.06 (m, 1 H), 7.99 (m, 1 H), 7.89 (m, 2 H), 7.62(d, J = 8.0 Hz, 2 H), 7.47 (m, 2 H), 7.06 (m, 2 H), 6.90 (m, 1 H), 6.68(d, J = 5.5 Hz, 1 H), 4.22 (m, 2 H), 3.84 (s, 3 H), 3.63 (s, 2 H), 3.57(m, 2 H), 3.30 (m, 3 H), 3.12 (m, 2 H) (presumably bis- trifluoroacetatesalt). MS (m/z): 615.3 (M + H). 168 61

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.59 (s, 1 H), 10.21 (s, 1 H), 8.51(d, J = 5.3 Hz, 1 H), 8.21 (s, 1 H). 8.12 (s, 1 H), 7.87 (m, 2 H), 7.77(m, 1 H), 7.75 (m, 1 H), 6.61 (d, J = 8.6 Hz, 3 H), 7.45 (m, 2 H), 7.33(m, 2 H), 7.05 (m, 1 H), 6.65 (m, 1 H), 4.0 (m, 2 H), 3.6 (m, 3 H), 3.33(s, 3 H), 2.80 (m, 2 H), (presumably monoformate salt). MS (m/z): 603.3(M + H). 170 63

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.00- 11.70 (m, 1 H). 8.53 (d, J =5.3 Hz, 1 H), 8.04 (s, 1 H), 8.02 (bd, J = 12.7 Hz, 1 H), 7.84 (d, J =8.2 Hz, 2 H), 7.58-7.51 (m, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.39-7.26(m, 5 H), 6.65 (dd, J = 5.5, 0.8 Hz, 1 H), 3.84 (s, 2 H), 3.83 (d, J =14.1 Hz, 1 H), 3.75 (d, J = 14.1 Hz, 1 H), 3.27 (dd, J = 9.3, 6.4 Hz, 1H), 3.24 (s, 3 H), 3.19 (dd, J = 9.4, 5.5 Hz, 1 H), 2.83- 2.73 (m, 1 H),0.98 (d, J = 6.3 Hz, 3 H), two NH are missing. MS (m/z): 615.3 (M + H).171 64

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.53 (d, J = 5.5 Hz, 1 H), 8.04 (s, 1H), 8.02 (bd, J = 12.0 Hz, 1 H), 7.84 (d, J = 8.2 Hz, 2 H), 7.59-7.51(m, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.42-7.35 (m, 2 H), 7.23- 7.15 (m,2 H), 6.66 (dd, J = 5.4, 0.7 Hz, 1 H), 3.84 (s, 2 H), AB system (□_(A) =3.83, □_(B) = 3.75, J_(AB) = 14.2 Hz, 2 H), 3.27 (dd, J = 9.3, 6.4 Hz, 1H), 3.24 (s, 3 H), 3.19 (dd, J = 9.2, 5.5 Hz, 1 H), 2.82-2.73 (m, 1 H),0.98 (d, J = 6.3 Hz, 3 H), three NH are missing. MS (m/z): 633.2 (M +H). 172 65

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.39 (s, 1 H), 9.99 (s, 1 H), 8.51(d, J = 5.5 Hz, 1 H), 8.15 (s, 1 H), 8.05 (s, 1 H), 7.91 (dd, J = 13.1,2.3 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 2 H), 7.65- 7.60 (m, 2 H), 7.55-7.44(m, 4 H), 7.34-7.28 (m, 2 H), 7.07 (tt, J = 7.4, 1.2 Hz, 1 H), 6.61 (dd,J = 5.4, 0.9 Hz, 1 H), AB system (□_(A) = 3.90, □_(B) = 3.83, J = 14.0Hz, 2 H), one CH ₂ is overlapped with peak of residual water, 3.26 (s, 3H), 2.92-2.82 (m, 1 H), 1.52- 1.43 (m, 4 H), 1.03 (d, J = 6.5 Hz, 3 H),one NH is missing. MS (m/z): 625.3 (M + H). (presumably mono-formatesalt). 174 67

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.54 (d, J = 5.3 Hz, 1 H), 8.05 (s, 1H), 8.02 (d, J = 11.9 Hz, 1 H), 7.86 (s, 1 H), 7.76 (d, J = 7.4 Hz, 1H), 7.54 (bs, 2 H), 7.49-7.34 (m, 4 H), 7.19 (t, J = 8.9 Hz, 2 H), 6.67(d, J = 5.3 Hz, 1 H), 3.90- 3.74 (m, 4 H), 3.32-3.16 (m, 5 H), 2.79(hex, J = 6.0 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3 H), three NH are missing.MS (m/z): 633.2 (M + H). 175 68

¹H NMR (400 MHz, MeOH-d₄) δ (ppm): Mixture of rotamers, 12.46 (s, 1 H),11.83 (s, 1 H), 8.53 (dd, J = 5.5, 2.0 Hz, 1 H), 8.03 (s, 1 H), 8.01(dd, J = 12.3, 2.0 Hz, 1 H), 7.79 (dd, J = 17.6, 8.4 Hz, 1 H), 7.70 (d,J = 1.6 Hz, 1 H), 7.57-7.49 (m, 2 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.37(dd, J = 8.8, 5.7 Hz, 2 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.17 (t, J = 9.0Hz, 2 H), 6.66 (d, J = 5.5 Hz, 1 H), 4.69 and 4.60 (2 s, 2 H), 3.82 (s,2 H), 3.48-3.41 (m, 4 H), 3.21 and 3.19 (2 s, 3 H), 2.12 and 2.02 (2s, 3H). MS (m/z): 661.2 (M + H). 178 71

¹H NMR (400 MHz, d₆ DMSO) δ (ppm): 8.54 (d, J = 5.2 Hz, 1 H), 8.05 (s, 1H), 8.02 (d, J = 12.0 Hz, 1 H), 7.85 (s, 1 H). 7.77 (d, J = 7.2 Hz, 1H), 7.59-7.51 (m, 2 H), 7.48-7.35 (m, 4 H), 7.19 (t, J = 8.8 Hz, 2 H),6.67 (d, J = 5.2 Hz, 1 H), 3.84 (s, 2 H), 3.80 (s, 2 H), 3.42 (t, J =5.6 Hz, 2 H), 3.24 (s, 3 H), 2.68 (t, J = 5.6 Hz, 2 H). MS (m/z): 619.2(M + H) 179 72

¹H NMR (400 MHz, d₆ DMSO) δ (ppm): 11.07 (s, 1 H), 10.63 s, 1 H), 8.51(d, J = 5.6 Hz, 1 H), 8.05 (s, 1 H), 7.87 (bs, 1 H), 7.83 (dd, J = 12.8,2.4 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.52-7.40 (m, 4 H), 7.39-7.34(dd, J = 8.8, 5.6 Hz, 2 H), 7.18 (t, J = 8.8 Hz, 2 H), 6.63 (d, J = 5.6Hz, 1 H), 3.82 (s, 2 H), 3.75 (s, 2 H), 3.43 (t, J = 5.6 Hz, 2 H), 3.25(s, 3 H), 2.70 (t, J = 5.6 Hz, 2 H). MS (m/z): 603.2 (M + H). 180 73

¹H NMR (400 MHz, d₆ DMSO) δ (ppm): 12.56 (bs, 1 H), 11.76 (bs, 1 H),8.54 (d, J = 5.2 Hz, 1 H), 8.09-8.03 (m, 2 H), 7.91 (s, 1 H), 7.82 (d, J= 7.6 Hz, 1 H), 7.59- 7.43 (m, 4 H), 7.28 (td, J = 7.8, 1.6 Hz, 1 H),7.23 (dd, J = 7.6, 1.6 Hz, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.94 (td, J= 7.6, 1.2 Hz, 1 H), 6.69 (d, J = 5.2 Hz, 1 H), 3.92 (s, 2 H), 3.82 (s,2 H), 3.79 (s, 3 H), 3.47 (t, J = 5.6 Hz, 2 H), 3.26 (s, 3 H), 2.81 (t,J = 5.6 Hz, 2 H). MS (m/z): 631.4 (M + H). 181 74

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.50 (s, 1 H), 11.85 (s, 1 H), 8.55(d, J = 5.6 Hz, 1 H), 8.07 (s, 1 H), 8.03 (d, J = 13.6 Hz, 1 H), 7.92(s, 1 H), 7.87-7.82 (m, 1 H), 7.59-7.44 (m, 4 H), 7.39-7.26 (m, 4 H),6.68 (d, J = 5.6 Hz, 1 H), 3.95 (bs, 2 H), 3.83 (s, 2 H), 3.45-3.25 (m,2 H, hidden under water signal), 3.15-3.00 (m, 5 H). MS (m/z): 649.4(M + H). 182 75

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1 H), 11.83 (s, 1 H), 8.54(d, J = 5.2 Hz, 1 H), 8.06 (s, 1 H), 8.02 (d, J = 12.4 Hz, 1 H), 7.86(s, 1 H), 7.78 (d, J = 7.6 Hz, 1 H), 7.59-7.51 (m, 2 H), 7.47 (t, J =7.6 Hz, 1 H), 7.43 (s, 1 H), 7.42-7.35 (m, 2 H), 7.19 (t, J = 8.8 Hz, 2H), 6.67 (d, J = 5.2 Hz, 1 H), 3.84 (s, 2 H), 3.80 (s, 2 H), 3.28 (t, J= 6.8 Hz, 2 H), 3.04 (s, 3 H), 2.93 (t, J = 6.8 Hz, 2 H). MS (m/z):667.2 (M + H). 183 76

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1 H), 11.84 (s, 1 H), 8.53(d, J = 5.2 Hz, 1 H), 8.05 (s, 1 H), 8.02 (d, J = 12.4 Hz, 1 H),7.86 (d,J = 8.0 Hz, 2 H), 7.58-7.51 (m, 2 H), 7.47 (d, J = 8.0 Hz, 2 H),7.41-7.35 (m, 2 H), 7.22- 7.15 (m, 2 H), 6.66 (d, J = 5.2 Hz, 1 H), 3.84(s, 2 H), 3.77 (s, 2 H), 2.27 (t, J = 6.8 Hz, 2 H), 3.03 (s, 3 H), 2.92(t, J = 6.8 Hz, 2 H). MS (m/z): 667.2 (M + H). 184 77

¹1 H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.50 (s, 1 H), 11.85 (s, 1 H),8.53 (d, J = 5.4 Hz, 1 H), 8.05 (s, 1 H), 8.03 (d, J = 12.4 Hz, 1 H),7.86 (d, J = 8.4 Hz, 2 H), 7.58-7.51 (m, 2 H), 7.46 (d, J = 8.4 Hz, 2H), 7.39-7.26 (m, 5 H), 6.66 (d, J = 5.4 Hz, 1 H), 3.83 (s, 2 H), 3.77(s, 2 H), 3.27 (t, J = 6.8 Hz, 2 H), 3.03 (s, 3 H), 2.92 (t, J = 6.8 Hz,2 H). MS (m/z): 649.2 (M + H). 186 79

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.45 (s, 1 H), 10.00 (s, 1 H), 9.65(bs, 2 H), 8.61 (d, J = 5.6 Hz, 1 H), 8.18 (s, 1 H), 8.03 (d, J = 8.4Hz, 2 H), 7.94 (dd, J = 13.2, 2.0 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 2 H),7.63 (dd, J = 8.4, 1.2 Hz, 1 H), 7.55 (dd, J = 8.8, 2.0 Hz, 1 H), 7.51(t, J = 8.8 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 2 H), 7.07 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 5.6 Hz, 1 H), 4.29 (t, J = 5.2 Hz, 2 H), 3.67-3.60 (m,2 H), 3.44-3.34 (m, 2 H), 3.15 (s, 3 H), 1.53-1.45 (m, 4 H) (presumablyhydrochloride salt). MS (m/z): 659.2 (M + H). 187 80

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.31 (s, 1 H), 8.50 (d, J = 5.6 Hz,1 H), 8.19 (s, 1 H), 8.04 (s, 1 H), 7.85 (d, J = 8.4 Hz, 2 H), 7.80 (d,J = 12.8 Hz, 1 H), 7.55-7.28 (m, 10 H), 6.62 (d, J = 5.6 Hz, 1 H), 3.77(s, 2 H), 3.27 (t, J = 6.8 Hz, 2 H), 3.24-3.19 (m, 5 H), 3.03 (s, 3 H),2.92 (t, J = 6.8 Hz, 2 H) (presumably formate salt). MS (m/z): 647.2(M + H). 192 85

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.41 (s, 1 H), 9.97 (s, 1 H), 8.54(d, J = 5.6 Hz, 1 H), 8.14 (s, 0.5 H, formate), 8.08 (s, 1 H), 8.06 (s,1 H), 7.96 (dt, J = 7.2, 1.6 Hz, 1 H), 7.92 (dd, J = 13.2, 2.0 Hz, 1 H),7.66- 7.44 (m, 6 H), 7.31 (t, J = 8.0 Hz, 2 H), 7.08 (t, J = 8.0 Hz, 1H), 6.65 (d, J = 5.6 Hz, 1 H), 4.24 (s, 2 H), 3.60 (t, J = 5.2 Hz, 2 H),3.32 (s, 3 H), 3.13 (t, J = 5.2 Hz, 2 H), 1.53-1.44 (m, 4 H)(semiformate salt). MS (m/z): 611.3 (M + H). 193 86

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.59 (s, 1 H), 10.23 (s, 1 H), 9.01(bs, 2 H), 8.54 (d, J = 5.6 Hz, 1 H). 8.09 (s, 1 H), 8.07 (s, 1 H), 7.98(dt, J = 7.2, 1.6 Hz, 1 H), 7.90 (dd, J = 12.8, 2.4 Hz, 1 H), 7.64-7.54(m, 4 H), 7.51 (t, J = 8.8 Hz, 1 H), 7.45 (dd, J = 8.8, 2.4 Hz, 1 H),7.33 (t, J = 8.0 Hz, 2 H), 7.07 (1, J = 7.2 Hz, 1 H), 6.69 (d, J = 5.6Hz, 1 H), 4.30-4.24 (m, 2 H), 3.61 (t, J = 5.6 Hz, 2 H), 3.52 (s, 2 H),3.32 (s, 3 H), 3.21-3.13 (m, 2 H) (probably formate salt). MS (m/z):585.3 (M + H). 194 87

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.51 (s, 1 H), 11.86 (s, 1 H), 8.90(bs, 2 H), 8.56 (d, J = 5.6 Hz, 1 H), 8.16 (s, 1 H), 8.06- 7.99 (m, 3H), 7.63 (d, J = 8.4 Hz, 2 H), 7.60-7.52 (m, 2 H), 7.40-7.26 (m, 5 H),6.69 (dd, J = 5.2, 0.8 Hz, 1 H), 4.28-4.23 (m, 2 H), 3.84 (s, 2 H),3.22-3.14 (m, 2 H), 2.76 (t, J = 7.2 Hz, 2 H), 2.11 (s, 3 H) (presumablyformate salt). MS (m/z): 617.2 (M + H). 195 88

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1 H), 11.84 (s, 1 H), 8.54(d, J = 5.6 Hz, 1 H), 8.14 (s, 1 H), 8.10 (s, 1 H), 8.02 (d, J = 14.0Hz, 1 H), 7.93 (d, J = 8.4 Hz, 2 H), 7.58-7.52 (m, 4 H), 7.41-7.35 (m, 2H), 7.22-7.15 (m, 2 H), 6.67 (dd, J = 5.6, 0.8 Hz, 1 H), 4.02 (s, 2 H),3.84 (s, 28), 2.95 (t, J = 7.2 Hz, 2 H), 2.68 (t, J = 7.2 Hz, 2 H), 2.08(s, 3 H) (presumably formate salt). MS (m/z): 635.2 (M + H). 205 98

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.50 (s, 1 H), 11.85 (s, H), 8.67(t, J = 5.2 Hz, 1 H), 8.56 (d, J = 5.6 Hz, 1 H), 8.20 (s, 1 H),8.06-7.94 (m, 5 H), 7.59-7.52 (m, 2 H), 7.39- 7.33 (m, 4 H), 7.33-7.26(m, 1 H), 6.70 (d, J = 5.6 Hz, 1 H), 3.84 (s, 2 H), 3.51-3.42 (m, 4 H),3.28 (s, 3 H). MS (m/z): 615.2 (M + H). 207 100

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.42 (s, 1 H), 9.97 (s, 1 H), 9.22(s, 2 H), 8.58 (d, J = 5.8 Hz, 1 H), 8.14 (s, 1 H), 7.99 (d, J = 8.4 Hz,2 H), 7.92 (dd, , J = 13.1, 2.1 Hz, 1 H), 7.67 (d, J = 8.6 Hz, 2 H),7.61 (dd, J = 8.6, 1.0 Hz, 2 H), 7.53 (dd, J = 9.2, 2.3 Hz, 1 H), 7.48(t, J = 8.7 Hz, 1 H), 7.29 (m, 2 H), 7.05 (m, 1 H), 6.72 (d, J = 5.6 Hz,1 H), 4.21 (t, J = 5.6 Hz, 2 H), 3.61 (t, J = 5.1 Hz, 2 H), 3.38 (s, 3H), 3.09 (m, 2 H), 1.48 (m, 4 H) (presumably hydro chloride salt). MS(m/z): 611.3 (M + H). 208 101

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.28 (s, 1 H), 10.12 (s, 1 H), 9.22(s, broad, 2 H), 8.56 (d, J = 5.6 Hz, 1 H), 8.15 (s, 1 H), 8.04-7.97 (m,3 H), 7.86 (d, J = 13.5 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 2 H), 7.56 (m, 2H), 7.05 (m, 2 H), 6.91 (m, 1 H), 6.69 (d, J = 5.6 Hz, 1 H), 4.21 (t, 2H), 3.81 (s, 3 H), 3.61 (t, 2 H), 3.29 (s, 3 H), 3.09 (m, 2 H), 1.58 (m,4 H) (presumably hydro chloride salt). MS (m/z): 641.3 (M + H). 209 102

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.41 (s, 1 H), 11.89 (s, 1 H), 9.12(s, broad, 2 H), 8.59 (d, J = 5.6 Hz, 1 H), 8.14 (s, 1 H), 8.04-7.96 (m,3 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.54 (m, 2 H), 7.38 (dt, J = 7.5, 1.6Hz, 1 H), 7.35-7.31 (m, 1 H), 7.21-7.15 (m, 2 H), 6.76 (d, J = 5.1 Hz, 1H), 4.20 (t, J = 5.3 Hz, 2 H), 3.91 (S, 2 H), 3.60-3.53 (m, 2 H), 3.29(s, 3), 3.10 (m, 4 H) (presumably hydrochloride salt). MS (m/z): 619.1(M + H). 211 104

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.60 (s, 1 H), 10.20 (s, 1 H), 8.48(d, J = 5.3 Hz, 1 H), 8.00 (s, 1 H), 7.88-7.10 (m, 3 H), 7.58 (d, J =7.6 Hz, 2 H), 7.48 (t, J = 8.7 Hz, 1 H), 7.42 (dd, J = 9.0, 1.8 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 2 H), 7.05 (t, J =7.3 Hz, 1 H), 6.61 (d, J = 5.3 Hz, 1 H), 3.26 (s, 3 H), 3.00-2.86 (m, 6H) (presumably formate salt). MS (m/z): 599.3 (M + H) 212 105

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.50 (s, 1 H), 11.84 (s, 1 H), 8.68(s, br, 2 H), 8.45 (d, J = 5.5 Hz, 1 H), 8.02 (dd, J = 12.5, 2.4 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1 H), 7.81 (d, J = 1.2 Hz, 1 H), 7.70 (s, 1 H),7.55-7.48 (m, 2 H), 7.34- 7.32 (m, 4 H), 7.30-7.22 (m, 1 H), 6.58 (dd, J= 5.5, 0.8 Hz, 1 H), 4.34 (t, J = 6.0 Hz, 2 H), 3.81 (s, 2 H), 3.55 (t,J = 5.0 Hz, 1 H), 3.34-3.30 (m, 1 H), 3.15 (m, 4 H) (presumably formatesalt). MS (m/z): 605.3 (M + H). 213 106

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1 H), 11.83 (s, 1 H), 8.70(s, br, 2 H), 8.48 (d, J = 5.5 Hz, 1 H), 8.02 (dd, J = 2.9, 2.2 Hz, 1H), 7.97 (d, J = 1.2 Hz, 1 H), 7.84 (d, J = 1.2 Hz, 1 H), 7.71 (s, 1 H),7.56-7.38 (m, 2 H), 7.38-7.34 (m, H), 7.20-7.15 (m, 2 H), 6.63 (dd, J =5.7, 0.6 Hz, 1 H), 4.35 (t, J = 6.0 Hz, 2 H), 3.82 (s, 2 H), 3.56 (t, J= 5.0 Hz, 2 H), 3.44-3.41 (m, 2 H), 3.31 (s, 3 H), 3.15-3.12 (m, 2 H)(presumably trifluoroacetic acid salt). MS (m/z): 623.2 (M + H). 215 108

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1 H), 11.84 (s, 1 H), 9.03(s br, 2 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.02 (dd, J = 13.3, 2.0 Hz, 1H), 7.87 (s, 1 H), 7.61 (d, J = 3.5 Hz, 1 H), 7.54-53 (m, 2 H),7.35-7.32 (m, 5 H), 7.29-7.26 (m, 1 H), 6.68 (dd, J = 5.5, 0.8 Hz, 1 H),4.43 (t, J = 5.0 Hz, 2 H), 3.81 (s, 2 H), 3.57 (t, J = 5.1 Hz, 2 H),3.14-3.12 (m, 2 H) (presumably trifluoroacetic acid salt). MS (m/z):607.1 (M + H). 218 111

¹H NMR (400 MHz, CH3CN-d₃) δ (ppm): 12.51 (s, 1 H), 11.85 (s, 1 H), 9.3(br.s, 1 H), 8.74 (d, J = 1.5 Hz, 1 H), 8.61 (d, J = 5.7 Hz, 1 H), 8.44(s, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 8.14 (dd, J = 8.2, 1.9 Hz, 1 H),8.04 (d, J = 13.1 Hz, 1 H), 7.56 (m, 2 H), 7.25-7.35 (m, 5 H), 6.77 (d,J = 5.2 Hz, 1 H), 4.25 (m, 2 H), 3.82 (s, 2 H), 3.61 (m, 2 H), 3.30 (s,3 H), 3.13 (m, 2 H) (presumably HCl trisalt). MS (m/z): 602.2 (M + H).219 112

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.53 (s, 1 H), 11.87 (s, 1 H), 9.48(br.s, 2 H), 8.69 (d, J = 5.9 Hz, 1 H), 8.51 (s, 1 H), 8.33 (d, J = 7.8Hz, 1 H), 8.06 (m, 2 H), 7.60 (m, 3 H), 7.2-7.4 (m, 7 H), 6.87 (d, J =5.7 Hz, 1 H), 4.43 (s, 2 H), 3.83 (s, 3 H), 3.70 (m, 2 H), 3.55 (s, 2 H)(presumably HCl trisalt). MS (m/z): 602.2 (M + H). 220 113

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.59 (s, 1 H), 11.77 (s, 1 H), 9.61(br.s, 1 H), 8.81 (s, 1 H), 8.78 (d, J = 6.1 Hz, 1 H), 8.49 (s, 1 H),8.45 (d, J = 8.6 Hz, 1 H), 8.24 (d, J = 7.2 Hz, 1 H), 8.13 (d, J = 12.1Hz, 1 H), 7.62 (s, 2 H), 7.2-7.3 (m,, 2 H), 7.03 (d, J = 6.3 Hz, 1 H),6.98 (d, J = 8.0 Hz, 1 H), 6.90 (t, J = 7.2 Hz, 1 H), 4.26 (s, 2 H),3.6-4.0 (m, 4 H), 3.77 (s, 3 H), 3.29 (s, 3 H), 3.12 (s, 2 H)(presumably HCl trisalt). MS (m/z): 632.3 (M + H). 223 116

¹H NMR (400 MHz, MeOH-d₄) δ (ppm): 8.58 (d, J = 1.5 Hz, 1 H), 8.46 (d, J= 5.4 Hz, 1 H), 8.09 (s, 1 H), 8.06 (s, 1 H), 7.92 (dd, J = 8.2, 2.2 Hz,1 H), 7.75 (dd, J = 12.7, 2.2 Hz, 1 H), 7.25- 7.5 (m, 7 H), 3.88 (s, 2H), 3.53 (t, J = 5.1 Hz, 2 H), 3.35 (s, 3 H), 3.34 (s, 2 H), 2.81 (t, 2H) (presumably HCl salt). MS (m/z): 600.3 (M + H). 224 117

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.38 (s, 1 H), 9.99 (s, 1 H), 8.51(d, J = 5.5 Hz, 1 H), 8.35 (s, 1 H), 8.21 (br.s, 0.6 H), 8.12 (d, J =7.9 Hz, 1 H), 7.92 (m, 2 H), 7.62 (d, J = 7.6 Hz, 2 H), 7.46 (m, 3 H),7.30 (t, J = 7.7 Hz, 2 H), 7.06 (t, J = 7.2 Hz, 1 H), 6.61 (d, J = 5.3Hz, 1 H), 3.89 (s, 2 H), 3.24 (s, 3 H), 2.75 (t, J = 5.2 Hz, 2 H), 1.47(s, 4 H) (presumably as formate salt). MS (m/z): 612.2 (M + H). 225 118

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1 H), 8.59 (d, J = 5.5 Hz,1 H), 8.43 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H), 8.00 (t, J = 7.9 Hz, 1H), 7.88 (d, J = 13.7 Hz, 1 H), 7.56 (m, 4 H), 7.39 (m, 3 H), 6.72 (d, J= 4.9 Hz, 1 H), 3.95 (s, 2 H), 3.52 (t, J = 5.7 Hz, 2 H), 3.33 (s, 3 H),3.31 (s, 2 H), 3.27 (s, 3 H), 2.82 (t, J = 5.5 Hz, 3 H). MS (m/z): 618.2(M + H). 229 122

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.54 (d, J = 5.5 Hz, 1 H), 8.06 (s, 1H), 8.03-8.00 (m, 1 H), 7.97 (s, 1 H), 7.88-7.84 (m, 1 H), 7.54-7.50 (m,4 H), 7.35-7.32 (m, 4 H), 7.29- 7.26 (m, 1 H), 6.67 (d, J = 5.3 Hz, 1H), 4.11-4.02 (m, 2 H), 3.82 (s, 2 H), 3.40 (s, J = 5.5 Hz, 2 H), 3.28(s, 3 H), 3.16-3.11 (m, 1 H), 1.15 (d, J = 6.5 Hz, 3 H). MS (m/z): 615.2(M + H). 230 123

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.48 (br s, 1 H), 11.85 (br s, 1 H),8.53 (d, J = 5.5 Hz, 1 H), 8.18 (s, 1 H), 8.06 (s, 1 H), 8.02 (d, J =11.9 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.55-7.53 (m, 2 H), 7.49 (d, J= 8.4 Hz, 2 H), 7.40-7.36 (m, 2 H), 7.21-7.16 (m, 2 H), 6.65 (d, J = 5.3Hz, 1 H), 3.88 (s, 2 H), 3.84 (s, 2 H), 2.19 (septet, J = 3.7 Hz, 1 H),0.45-0.38 (m, 4 H) (presumably formate salt). MS (m/z): 601.2 (M + H).231 124

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.39 (s, 1 H), 10.00 (s, 1 H), 8.50(d, J = 5.5 Hz, 1 H), 8.12 (s, 1 H), 7.99 (s, 1 H), 7.91 (d, J = 12.9Hz, 1 H), 7.85-7.82 (m, 2 H), 7.65-7.62 (m, 2 H), 7.54-7.45 (m, 4 H),7.33- 7.29 (m, 2 H), 7.09-7.04 (m, 1 H), 6.60 (d, J = 5.5, 1 H), 3.78(s, 2 H), 2.06 (sept, J = 3.5, 1 H), 0.39-0.27 (m, 4 H) (presumablyformate salt) . MS (m/z): 593.2 (M + H). 233 126

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1 H), 9.97 (s, 1 H), 8.49(d, J = 5.5 Hz, 1 H), 8.03 (s, 1 H), 7.90 (d, J = 13.3 Hz, 1 H),7.86-7.83 (m, 2 H), 7.63-7.60 (m, 2 H), 7.52- 7.43 (m, 4 H), 7.32-7.27(m, 2 H), 7.07-7.03 (m, 1 H), 6.59 (d, J = 5.5 Hz, 1 H), 3.84-3.82 (m, 2H), 3.27- 3.15 (m, 2 H), 3.02 (quint, J = 6.7, 1 H), 1.46 (br s, 4 H).MS (m/z): 635.2 (M + H). 235 128

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.64 (s, 1 H), 10.26 (s, 1 H), 8.57(d, J = 1.4 Hz, 1 H), 8.52 (d, J = 5.3 Hz, 1 H), 8.32 (s, 1 H), 8.23 (d,J = 8.0 Hz, 1 H), 7.91 (s, 1 H), 7.89-7.87 (m, 1 H), 7.63-7.60 (m, 2 H),7.50 (t, J = 9.0 Hz, 1 H), 7.45 (dd, J = 6.9, 0.8 Hz, 1 H), 7.34-7.30(m, 2 H), 7.09-7.04 (m, 1 H), 6.68 (dd, J = 5.3, 0.8 Hz, 1 H), 3.78 (s,2 H), 3.52 (s, 2 H), 3.41 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.65 (t,J = 5.5 Hz, 2 H). MS (m/z: 586.3 (M + H). 236 129

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.28 (s, 1 H), 8.58 (s, 1 H), 8.52(d, J = 5.3 Hz, 1 H), 8.33 (s, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 8.15 (s,1 H), 7.91 (dd, J = 8.0, 2.0 Hz, 1 H), 7.79 (dd, J = 12.9, 2.0 Hz, 1 H),7.49-7.43 (m, 3 H), 7.33- 7.27 (m, 3 H), 6.66 (d, J = 5.3 Hz, 1 H), 3.92(s, 2 H), 3.42 (t, J = 5.7 Hz, 2 H), 3.25 (s, 3 H), 3.23 (s, 2 H), 3.19(s, 3 H), 2.69 (t, J = 5.5 Hz, 2 H). MS (m/z): 618.3 (M + H). 237 130

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.61 (s, 1 H); 10.32 (s, 1 H); 8.57(s, J = 1.4, 1 H); 8.52 (d, J = 5.5, 1 H); 8.33 (s, 1 H); 8.23 (d, J =8.0, 1 H); 7.91 (d, J = 2.2, 1 H); 7.89-7.86 (m, 1 H); 7.66-7.60 (m, 2H); 7.51 (t, J = 8.8, 1 H); 7.44 (dd, J = 9.0, 2.0, 1 H); 7.20- 7.14 (m,2 H); 6.68 (d, J = 5.5, 1 H); 3.78 (s, 2 H); 3.51 (s, 2 H); 3.41 (t, J =5.7, 2 H); 3.24 (s, 3 H); 2.65 (t, J = 5.7, 2 H). MS (m/z): 604.2 (M +H). 244 137

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.27 (s, 1 H), 11.94 (s, 1 H), 9.50(s, 2 H), 8.77 (s, 1 H), 8.72 (m, 1 H), 8.41 (m, 2 H), 8.21 (m, 1 H),8.10 (m, 1 H), 7.55 (m, 1 H), 7.36 (m, 2 H), 7.25 (m, 1 H), 7.15 (m, 3H), 6.95 (m, 1 H), 4.21 (m, 2 H), 3.83 (s, 3 H), 3.63 (m, 2 H), 3.13 (m,2 H) (presumably trihydrochloride salt). MS (m/z): 620.1 (M + H). 252145

¹H NMR (DMSO-d₆) d (ppm) 1 H: 9.89 (s, 1 H); 9.41 (s, 1 H); 8.56 (s, 1H); 8.51 (d, J = 5.5, 1 H); 8.32 (s, 1 H); 8.23 (d, J = 8.0, 1 H); 7.89(dd, J = 10.0, 1.8, 1 H); 7.55 (dd, J = 13.1, 2.3, 1 H); 7.46 (t, J =9.0, 1 H); 7.30- 7.27 (m, 1 H); 6.66 (d, J = 5.3, 1 H); 6.51 (s, 1 H);3.77 (s, 2 H); 3.40 (t, J = 5.7, 2 H); 3.23 (s, 3 H); 2.65 (t, J = 5.5,2 H); 1.29 (s, 9 H). LRMS (ESI): (calc.) 591.2 (found) 591.2 (MH)⁺ 253146

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.60 (s, 1 H), 9.07 (d, J= 2.7 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1 H), 8.59 (dd, J = 7.1, 2.3 Hz, 1 H), 8.55 (d,J = 5.5 Hz, 1 H), 8.41 (s, 1 H), 8.34 (d, J = 8.2 Hz, 1 H), 8.03 (dd, J= 8.1, 2.1 Hz, 1 H), 7.79 (dd, J = 13.1, 2.5 Hz, 1 H), 7.58- 7.40 (m, 3H), 7.28 (bd, J = 8.6 Hz, 1 H), 6.70 (d, J = 5.3 Hz, 1 H), 4.13 (bs, 2H), 3.54 (t, J = 5.2 Hz, 2 H), 3.30 (s, 3 H), 3.08-12.96 (m, 2 H), oneNH is not observed (presumably trifluoroacetate salt). MS (m/z): 630.2(M + H). 254 147

¹H NMR (400 MHz, DMSO-d₆) □ (ppm): 10.42 (s, 1 H), 10.01 (s, 1 H), 8.49(d, J = 5.3 Hz, 1 H), 8.15 (s, 1 H, formate salt), 7.90 (dd, J = 13.3,2.0 Hz, 1 H), 7.77 (s, 1 H), 7.68-7.60 (m, 2 H), 7.54-7.43 (m, 2 H),7.20- 7.11 (m, 2 H), 7.10 (d, J = 3.3 Hz, 1 H), 6.60 (d, J = 5.5 Hz, 1H), 6.50 (d, J = 3.3 Hz, 1 H), 3.82 (s, 2 H), one CH₂ is masked by waterpeak, 3.24 (s, 3 H), 2.74 (t, J = 5.7 Hz, 2 H), 1.51-1.43 (m, 4 H), oneNH is missing. MS (m/z): 619.2 (M + H). 255 148

¹H NMR (400 MHz, DMSO-d₆) □ (ppm) (ppm): mixture of rotamers, 10.42 (s,1 H), 10.02 (s, 1 H), 8.53- 8.47 (m, 1 H), 8.06 and 8.02 (2 s, 1 H),7.95-7.77 (m, 3 H), 7.68-7.60 (m, 2 H), 7.55- 7.43 (m, 2 H), 7.41 and7.35 (2 d, J = 8.2 Hz, 2 H), 7.15 (t, J = 8.8 Hz, 2 H), 6.60 (t, J = 5.3Hz, 1 H), 4.73-4.17 (m, 3 H), 3.42-3.23 (m, 2 H), 3.16 (s, 3 H), 2.16and 1.93 (2 s, 3 H), 1.53-1.42 (m, 4 H), 1.09-1.00 (m, 3 H). MS (m/z):685.3 (M + H) 256 149

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.36 (br, 1 H), 9.37 (br, 1 H),8.57-8.49 (m, 3 H), 8.38 (s, 1 H), 8.23 (dd, J = 8.2 Hz, 1 H), 7.95-7.88(m, 3 H), 7.78 (d, J = 12.9 Hz, 1 H), 7.59-7.56 (m, 1 H), 7.52- 7.49 (m,2 H), 7.45-7.41 (m, 2 H), 6.66 (d, J = 5.5 Hz, 1 H), 3.78 (s, 2 H), 3.41(t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.65 (t, J = 5.7 Hz, 2 H), 2.28(br, 1 H). MS (m/z): 587.3 (M + H). 257 150

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.51 (d, J = 5.5 Hz, 1 H), 8.32 (s, 1H), 8.11 (d, J = 7.7 Hz, 2 H), 7.90 (m, 2 H), 7.62 (m, 2 H), 7.45 (m, 3H), 7.13 (t, J = 8.8 Hz, 2 H), 6.61 (d, J = 5.1 Hz, 1 H), 3.86 (s, 2 H),2.72 (m, 2 H), 1.41 (br.s, 4 H). MS (m/z): 630.3 (M + H). 258 151

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): mixture of rotamers, 10.92 (s, 1 H),8.52 (dd, J = 5.5, 3.5 Hz, 1 H), 8.36 (s, 1 H), 8.07 and 8.03 (2 s, 1H), 7.96 (dd, J = 13.7, 2.0 Hz, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.82(d, J = 8.2 Hz, 1 H), 7.67-7.51 (m, 7 H), 7.41 (d, J = 8.2 Hz, 1 H),7.36 (d, J = 8.2 Hz, 1 H), 6.67 (t, J = 5.5 Hz, 1 H), 4.74-4.16 (m, 3H), 3.42-3.24 (m, 2 H), 3.16 (s, 3 H), 2.16 and 1.93 (2 s, 3 H),1.09-1.01 (m, 3 H). MS (m/z): 718.3 (M + H). 259 152

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.92 (s, 1 H), 9.02 (s, 1 H), 8.57(d, J = 1.4 Hz, 1 H), 8.54 (d, J = 5.3 Hz, 1 H), 8.32 (s, 1 H), 8.26 (s,1 H), 8.24-8.17 (m, 2 H), 7.89 (dd, J = 8.0 Hz, 1 H), 7.44 (dd, J =11.6, 2.7, 1 H), 7.17-7.14 (m, 1 H), 6.74 (d, J = 5.5 Hz, 1 H), 6.54 (d,J = 1.0 Hz, 1 H), 3.78 (s, 2 H), 3.41 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3H), 2.65 (t, J = 5.7 Hz, 2 H), 2.37 (s, 3 H). MS (m/z): 549.1 (M + H).260 153

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.70 (s, 1 H), 11.73 (s, 1 H), 9.04(s, 2 H), 8.7 (s, 1 H), 8.64 (d, J = 8.8 Hz, 1 H), 8.56 (m, 1 H), 8.41(s, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.08 (m, 1 H), 7.36 (m, 2 H), 7.15(m, 3 H), 6.92 (m, 1 H), 6.75 (m, 1 H), 4.2 (m, 2 H), 3.82 (m, 5 H),3.58 (m, 2 H), 3.31 (s, 3 H), 3.15 (m, 2 H). MS (m/z): 632.1 (M + H).261 154

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.55 (s, 1 H), 8.50 (d, J = 5.3 Hz, 1H), 8.41 (s, 1 H), 8.30 (s, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 7.88 (dd, J8.0, 2.2 Hz, 1 H), 7.70 (dd, J = 13.0, 2.3 Hz, 1 H), 7.37-7.33 (m, 2 H),6.62 (dd, J = 5.3, 0.8 Hz, 1 H), 3.83 (sept, J = 6.7 Hz, 2 H), 3.76 (s,2 H), 3.39 (t, J = 5.7 Hz, 2 H), 3.23 (s, 3 H), 2.64 (t, J = 5.7 Hz, 2H), 1.25 (d, J = 6.7 Hz, 12 H). MS (m/z): 552.2 (M + H). 262 155

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.01 (s, 1 H), 8.76 (bs, 1 H), 8.57(d, J = 1.2 Hz, 1 H), 8.51 (d, J = 5.6 Hz, 1 H), 8.31 (s, 1 H), 8.23 (d,J = 8.4 Hz, 1 H), 8.20 (d, J = 8.8 Hz, 1 H), 7.89 (dd, J = 8.4, 1.6 Hz,1 H), 7.10 (d, J = 2.8 Hz, 1 H), 6.87 (dd, J = 8.8, 2.8 Hz, 1 H), 6.67(d, J = 5.6 Hz, 1 H), 6.52 (s, 1 H), 3.89 (s, 3 H), 3.78 (s, 2 H), 3.41(t, J = 5.6 Hz, 2 H), 3.24 (s, 3 H), 2.65 (t, J = 5.6 Hz, 2 H), 2.37 (s,3 H). MS (m/z): 561.1 (M + H). 263 156

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.86 (s, 1 H), 8.60 (d, J = 1.4 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1 H), 8.35 (s, 1 H), 8.31 (bs, 1 H), 8.27 (d, J= 8.2 Hz, 1 H), 7.94 (dd, J = 8.1, 2.1 Hz, 1 H), 7.90 (bd, J = 8.8 Hz, 1H), 7.65-7.51 (m, 5 H), 7.15 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J = 8.6,2.5 Hz, 1 H), 6.74 (d, J = 5.3 Hz, 1 H), 3.93-3.81 (m, 5 H), 3.45 (t, J= 5.6 Hz, 2 H), 3.26 (s, 3 H), 2.76 (bt, J = 5.1 Hz, 2 H). MS (m/z):675.2 (M + H). 264 157

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.67 (s, 1 H), 9.78 (s, 1 H), 8.54(d, J = 1.1 Hz, 1 H), 8.50 (d, J = 5.5 Hz, 1 H), 8.29 (s, 1 H),8.26-8.17 (m, 2 H), 7.87 (dd, J = 8.0, 2.0 Hz,, 1 H), 7.59-7.56 (m, 2H), 7.21-7.16 (m, 2 H), 7.12- 7.09 (m, 1 H), 6.84 (dd, J = 8.8, 2.5 Hz,1 H), 6.65 (d, J = 5.5 Hz, 1 H), 3.82 (s, 3 H), 3.76 (s, 2 H), 3.29 (m,2 H), 3.22 (s, 3 H), 2.64-2.62 158 (m, 2 H), 1.61-1.56 (m, 4 H). MS(m/z): 642.2 (M + H). 265 158

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.50 (s, 1 H), 8.60-8.55 (m, 2 H),8.34 (s, 2 H), 8.25 (d, J = 8.2 Hz, 1 H), 7.90 (dd, J = 8.2, 2.2 Hz, 1H), 7.84 (t, J = 8.8 Hz, 1 H), 7.65-7.52 (m, 5 H), 7.47 (dd, J = 11.1,2.6 Hz, 1 H), 7.24-7.19 (m, 1 H), 6.82 (d, J = 5.5 Hz, 1 H), 3.79 (s, 2H), 3.41 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H), 2.66 (t, J = 5.7 Hz, 2 H).MS (m/z): 663.2 (M + H). 266 159

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) (ppm): 9.26 (s, 1 H), 8.57 (d, J = 1.2Hz, 1 H), 8.52 (d, J = 5.6 Hz, 1 H), 8.32 (s, 1 H), 8.23 (d, J = 8.0 Hz,1 H), 7.91 (s, 1 H), 7.89 (d, J = 2.0 Hz, 1 H), 7.73 (dd, J = 13.2, 2.4Hz, 1 H), 7.43 (t, J = 8.8 Hz, 1 H), 7.29 (d, J = 8.8 Hz, 1 H), 6.65(dd, J = 5.6, 0.8 Hz, 1 H), 3.78 (s, 2 H), 3.41 (t, J = 5.6 Hz, 2 H),3.24 (s, 3 H), 2.65 (t, J = 5.6 Hz, 2 H), 2.30 (s, 3 H), 2.13 (s, 3 H).MS (m/z): 563.2 (M + H). 267 160

¹H NMR (400 MHz, DMSO-d₆) □ (ppm) (ppm): 9.69 (s, 1 H), 8.57 (d, J = 1.2Hz, 1 H), 8.53 (d, J = 5.6 Hz, 1 H), 8.33 (s, 1 H), 8.33 (s, 1 H), 8.24(d, J = 8.0 Hz, 1 H), 8.33 J = 8.0, 1.6 Hz, 1 H), 7.90 (dd, J = 8.0, 2.0Hz, 1 H), 7.78 (dd, J = 13.2, 2.4 Hz, 1 H), 7.45 (t, J = 9.2 Hz, 1 H),7.21 (d, J = 9.0 Hz, 1 H), 7.40 (dd, J = 8.4, 1.6 Hz, 1 H), 6.98 (td, J= 8.0, 1.6 Hz, 1 H), 6.91 (td, J = 8.0, 1.6 Hz, 1 H), 6.67 (d, J = 5.6Hz, 1 H), 3.90 (s, 3 H), 3.78 (s, 2 H), 3.41 (t, J = 5.6 Hz, 2 H), 3.24(s, 3 H), 2.65 (t, J = 5.6 Hz, 2 H). MS (m/z): 574.2 (M + H). 268 161

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.68 (s, 1 H), 9.31 (s, 1 H), 8.64(d, J = 1.6 Hz, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.36 (s, 1 H), 8.28 (d,J = 8.2 Hz, 1 H), 7.97 (dd, J = 8.2, 2.2 Hz, 1 H), 7.79 (dd, J = 13.5,2.5 Hz, 1 H), 7.44 (t, J = 9.1 Hz, 1 H), 7.34 (bs, 1 H), 7.31- 7.25 (m,2 H), 7.16 (t, J = 7.7 Hz, 1 H), 6.80 (d, J = 7.4 Hz, 1 H), 6.68 (dd, J= 5.5, 0.8 Hz, 1 H), 3.99 (s, 2 H), 3.49 (t, J = 5.4 Hz, 2 H), 3.27 (s,3 H), 2.87 (t, J = 5.4 Hz, 2 H), 2.28 (s, 3 H). MS (m/z): 558.1 (M + H).269 162

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.63 (s, 1 H), 9.22 (s, 1 H), 8.52(d, J = 5.5 Hz, 1 H), 8.36 (s, 1 H), 8.15 (d, J = 7.4 Hz, 1 H), 7.93 (t,J = 7.8 Hz, 1 H), 7.74 (dd,, J = 12.9, 2.5 Hz, 1 H), 7.46 (t, J = 8.0Hz, 2 H), 7.27 (m, 1 H), 6.64 (dd, J = 5.2, 0.8 Hz, 1 H), 6.55 (s, 1 H),3.94 (s, 2 H), 3.46 (t, J = 5.4 Hz, 2 H), 3.25 (s, 3 H), 2.81 (m, 2 H),2.37 (s, 3 H). MS (m/z): 549.1 (M + H). 270 163

¹H NMR (400 MHz, DMSO-d₆) □ (ppm) (ppm): 10.40 (s, 1 H), 10.02 (s, 1 H),8.51 (d, J = 5.28 Hz, 1 H), 7.89 (m, 2 H), 7.63 (m, 2 H), 7.48 (m, 2 H),7.15 (t, J = 8.80, 2 H), 6.95 (s, 1 H), 6.67 (d, J = 5.28 Hz, 1 H) k,3.91 (s, 3 H), 3.76 (s, 2 H), 3.40 (t, J = 5.68 Hz, 2 H), 3.24 (s, 3 H),2.68 (t, J = 5.68 Hz, 2 H), 1.46 (s, 4 H). MS (m/z): 633.7 (M + H). 271164

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.24 (bs, 2 H), 8.58 (d, J = 1.6 Hz,1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.33 (s, 1 H), 8.25 (d, J = 8.2 Hz, 1H), 8.02 (bs, 1 H), 7.91 (dd, J = 8.2, 2.2 Hz, 1 H), 7.77 (dd, J = 13.2,2.4 Hz, 1 H), 7.62 (bd, J = 8.6 Hz, 1 H), 7.54 (t, J = 7.9 Hz, 1 H),7.47 (t, J = 9.1 Hz, 1 H), 7.37-7.27 (m, 2 H), 6.67 (dd, J = 5.4, 0.7Hz, 1 H), 3.81 (s, 2 H), 3.42 (t, J = 5.6 Hz, 2 H), 3.25 (s, 3 H), 2.69(t, J = 5.7 Hz, 2 H). MS (m/z): 612.3 (M + H). 272 165

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.65 (s, 1 H); 8.57 (d, J = 1.6, 1H); 8.51 (d, J = 5.5, 1 H); 8.32 (s, 1 H); 8.23 (d, J = 8.6, 1 H); 7.90(dd, J = 8.2, 2.4, 1 H); 7.74-7.71 (m, 1 H); 7.40- 7.37 (m, 2 H); 6.64(d, J = 5.5, 1 H); 3.79 (s, 2 H); 3.41 (t, J = 5.7, 2 H); 3.24 (s, 3 H);2.95 (s, 6 H); 2.67 (t, J = 5.7, 2 H). MS (m/z): 496.3 (M + H) 273 166

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.66 (s, 1 H); 9.95 (s, 1 H); 8.55-8.53 (m, 2 H), 8.32 (s, 1 H), 8.23-8.21 (m, 1 H); 7.99 (t, J = 8.8, 1H); 7.88 (dd, J = 8.0, 2.2, 1 H); 7.61-7.58 (m, 2 H); 7.43-7.40 (m, 1H); 7.19- 7.13 (m, 3 H); 6.75 (d, J = 5.3, 1 H); 3.77 (s, 2 H); 3.40 (t,J = 5.7, 2 H); 3.23 (s, 3 H); 2.64 (t, J = 5.3, 2 H); 1.60- 1.55 (m, 4H). MS (m/z): 630.3 (M + H) 274 167

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.93 (s, 1 H), 8.56 (d, 1 H, J = 1.3Hz), 8.51 (d, 1 H, J = 5.5 Hz), 8.30 (s, 1 H), 8.22 (d, 1 H, J = 8.0Hz), 7.89 (dd, 1 H, J = 2.2 Hz, J = 8.0 Hz), 7.72 (dd, 1 H, J = 2.6 Hz,J = 13.5 Hz), 7.37 (t, 1 H, J = 9.2 Hz), 7.16 (m, 1 H), 6.63 (d, 1 H, J= 5.9 Hz), 6.43 (m, 1 H), 5.86 (m, 1 H), 5.17 (dd, 1 H, J = 1.8 Hz, J =17.2 Hz), 5.08 (dd, 1 H, J = 1.6 Hz, J = 10.2 Hz), 3.77 (s, 2 H), 7.74(t, 2 H, J = 5.5 Hz), 3.40 (t, 2 H, J = 5.7 Hz), 3.23 (s, 2 H), 2.64 (t,2 H, J = 5.6 Hz). MS (m/z): 508.3 (M + H). 275 168

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.03 (s, 1 H 0, 8.56 (m, 1 H), 8.50(d, 1 H, J = 5.5 Hz), 8.31 (s, 1 H), 8.22 (d, 1 H, J = 8.0 Hz), 7.89(dd, 1 H, J = 2.2 Hz, J = 8.0 Hz), 7.71 (dd, 1 H, J = 2.4 Hz, J = 13.5Hz), 7.1-7.4 (m, 6 H), 6.81 (t, 1 H, J = 6.0 Hz), 6.63 (dd, 1 H, J = 1.0Hz, J = 5.5 Hz), 4.36 (d, 2 H, J = 6.0 Hz), 3.77 (s, 2 H), 3.40 (t, 2 H,J = 5.5 Hz), 3.23 (s, 3 H), 2.64 (t, 2 H, J = 5.6 Hz). MS (m/z): 576.3(M + H). 276 169

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.66 (s, 1 H), 9.21 (s, 1 H), 8.49(d, J = 5.5 Hz, 1 H), 7.77 (s, 1 H), 7.74 (dd, J = 13.0, 2.4 Hz, 1 H),7.46 (t, J = 9.0 Hz, 1 H), 7.31-7.25 (m, 1 H), 7.09 (d, J = 3.3 Hz, 1H), 6.62 (d, J = 5.5 Hz, 1 H), 6.56 (d, J = 1.0 Hz, 1 H), 6.47 (d, J =3.3 Hz, 1 H), 3.78 (s, 2 H), 3.40 (t, J = 5.7 Hz, 2 H), 3.24 (s, 3 H),2.71 (t, J = 5.7 Hz, 2 H), 2.37 (d, J = 0.8 Hz, 3 H), one NH is missing.MS (m/z): 538.3 (M + H). 277 170

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.80 (s, 1 H); 8.57 (s, 1 H); 8.51(d, J = 5.5, 1 H); 8.31 (s, 1 H); 8.23 (d, J = 8.0, 1 H); 7.89 (dd, J =8.0, 1.5, 1 H); 7.73 (dd, J = −13.5, 2.2, 1 H); 7.38 (t, J = 9.0, 1 H);7.20 (d, J = 8.2, 1 H); 6.66-6.62 (m, 2 H); 3.78 (s, 2 H); 3.41 (t, J =5 .7, 2 H); 3.24 (s, 3 H); 2.65 (d, J = 5.7, 2 H); 2.57- 2.51 (m, 1 H);0.66-0.62 (m, 2 H); 0.44-0.41 (m, 2 H). MS (m/z): 508.3 (M + H). 278 171

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.74 (s, 1 H), 8.56 (d, 1 H, J = 0.6Hz), 8.51 (d, 1 H, J = 5.2 Hz), 8.30 (s, 1 H), 8.22 (d, 1 H, J = 7.8Hz), 7.89 (dd, 1 H, J = 1.9 Hz, J = 6.1 Hz), 7.36 (t, 1 H, J = 9.0 Hz),7.12 (m, 1 H), 6.63 (d, 1 H, J = 5.5 Hz), 6.26 (d, 1 H, J = 8.0 Hz),3.79 (s, 2 H), [3.44 (2 H)], 3.23 (s, 3 H), 2.66 (t, 2 H, 5.5 Hz), 1.80(m, 2 H), 1.66 (m, 2 H), 1.52 (m, 1 H), 2.1-2.4 (m, 6 H). MS (m/z):550.4 (M + H). 279 172

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.77 (s, 1 H); 9.35 (s, 1 H); 9.00(s, 2 H); 8.73 (d, J = 1.4, 1 H); 8.55 (d, J = 5.5, 1 H); 8.43 (s, 1 H);8.38 (d, J = 8.0, 1 H); 8.08 (dd, J = 8.2, 2.2, 1 H); 7.75 (dd, J =13.1, 2.5, 1 H); 7.47 (t, J = 9.0, 1 H); 7.31- 7.28 (m, 1 H); 6.70 (dd,J = 5.5, 0.7, 1 H); 6.56 (d, J = 1.0, 1 H); 4.28 (s, 2 H); 3.63 (t, J =5.0, 2 H); 3.50 (q, 7.0, 2 H); 3.16 (br s, 2 H); 2.38 (d, J = 0.7, 3 H);1.16 (t, J = 7.1, 3 H). MS (m/z): 563.3 (M + H). 280 173

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.45 (s, 1 H), 8.97 (br, s, 2 H),8.72 (d, 1 H, (dd, 1 H, J = J = 1.4 Hz), 8.62 (d, 1 H, J = 2.3 Hz), 8.57(d, 1 H, J = 5.5 Hz), 8.42 (s, H) 8.38 (d, 1 H, J = 8. Hz), 8.08 (dd, 1H, J = 2.2 Hz, J = 8.2 Hz), 7.93 (dd, 1 H, J = 2.0 Hz, J = 7.8 Hz), 7.78(dd, 1 H, J = 2.6 Hz, J = 13.3 Hz), 7.46 (t, 1 H, J = 9.0 Hz), 7.24 (m,1 H), 7.12 (dd, 1 H, J = 8 .4 Hz, J = 11.1 Hz), 6.84 (m, 1 H), 6.74 (d,1 H, J = 5.5 Hz), 4.27 (m, 2 H), [3.2-3.6 (9 H)], 2.27 (s, 3 H), 1.15(t, 3 H, J = 7.0 Hz). MS (m/z): 590.4 (M + H). 281 173

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.41 (s, 1 H); 10.02 (s, 1 H); 8.57(d, J = 1.4, 1 H); 8.52 (d, J = 5.5, 1 H); 8.32 (s, 1 H); 8.21 (d, J =9.8, 1 H); 7.94- 7.88 (m, 2 H); 7.67-7.62 (m, 2 H); 7.54-7.44 (m, 2 H);7.17-7.12 (m, 2 H); 6.65 (d, J = 5.5, 1 H); 3.79 (s, 2 H); 3.44 (t, J =5.9, 2 H); 3.41 (q, J = 7.7, 2 H); 2.66 (t, J = 5.7, 2 H); 1.10 (t, J =7.0, 3 H). MS (m/z): 644.4 (M + H). 282 175

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.67 (s, 1 H), 9.23 (s, 1 H), 8.52(d, J = 5.48 Hz, 1 H), 7.89 (s, 1 H), 7.73 (m, 1 H), 7.46 (t, J = 8.99Hz, 1 H), 7.28 (m, 1 H), 6.97 (s, 1 H), 6.68 (m, 1 H), 6.55 (s, 1 H),3.91 (s, 3 H), 3.7 (s, 2 H), 3.4− (m, 2 H), 3.29 (s, 3 H), 2.68 (t, J =5.67 Hz, 2 H), 2.37 (s, 3 H). MS (m/z): 552.3 (M + H). 283 176

¹1 H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.30 (s, 1 H), 8.48 (d, J = 5.5Hz, 1 H), 8.23 (s, 1 H, formate salt), 7.80 (bd, J = 13.5 Hz, 1 H), 7.76(s, 1 H), 7.52-7.28 (m, 7 H), 7.09 (d, J = 3.3 Hz, 1 H), 6.62 (d, J =5.5 Hz, 1 H), 6.47 (d, J = 3.3 Hz, 1 H), 3.78 (s, 2 H), one CH2 ismasked by water, 3.24 (s, 3 H), 3.25-3.20 (m, 5 H), 2.71 (t, J = 5.7 Hz,2 H), one NH is missing (as formate salt). MS (m/z): 589.3 (M + H). 284177

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.52 (s, 1 H); 8.58 (d, J = 1.6, 1H); 8.53 (d, J = 5.5, 1 H); 8.52- 8.48 (m, 1 H); 8.35 (s, 2 H); 8.32 (s,1 H); 8.23 (d, J = 8.0, 1 H); 7.88 (dd, J = 8.0, 1.8, 1 H); 7.81 (dd, J= 13.1, 2.4, 1 H); 7.52-7.40 (m, 3 H); 7.36-7.33 (m, 1 H); 6.68 (d, J =5.3, 1 H); 3.76 (s, 2 H); 3.50-3.40 (m, ~12 H, on top of water peak);2.80 (t, J = 7.4, 2 H); 2.54 (t, J = 7.1, 2 H); 1.73 (quint, J = 7.4, 2H); 1.68 (quint, J = 7.4, 2 H) (formate salt). MS (m/z): 775.5 (M + H).285 178

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.39 (s, 1 H); 8.58 (d, J = 1.6, 1H); 8.53 (d, J = 5.5, 1 H); 8.52- 8.50 (m, 1 H); 8.33 (s, 3 H); 8.23 (d,J = 8.0, 1 H); 7.89 (dd, J = 8.0, 1.8, 1 H); 7.80 (dd, J = 13.1, 2.4, 1H); 7.52- 7.40 (m, 3 H); 7.35-7.32 (m, 1 H); 6.68 (d, J = 5.5, 1 H);3.79 (s, 2 H); 3.56-3.48 (m, ~8 H, on top of water peak); 2.91 (t, J =5.3, 2 H); 2.66 (t, J = 5.6, 2 H) (as formate salt). MS (m/z): 703.4(M + H).

Example 1791-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(287)

To a solution of the 286 (150 mg, 0.233 mmol, obtained similarly tocompounds 47 or 47a, scheme 2) in DCM (1 ml) was added triethylsilane(37.9 mg, 0.326 mmol, 1.4 eq.), TEA (3.3 mg, 0.0033 mmol, 0.14 eq,) andPd(OAc)₂ (2.089 mg, 0.04 eq, 9.31 μM) and the reaction mixture washeated to reflux for 3 days. The reaction was stopped after 3 days (notcomplete) and the reaction mixture was extracted with EtOAc and water.The organic phase was collected, dried over Na₂SO₄, filtered andconcentrated. Purification by column chromatography (30% MeOH in EtOAc)afforded the title compound 287 (21 mg, 18% yield) as a yellow solid.Characterization of compound 287 is provided in the Table 6.

Example 1801-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(289) Step 1: tert-butyl(6-(7-(2-fluoro-4-ureidophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(288)

To a solution of compound 126 (3.0 g, 5.72 mmol) in AcOH (13.6 mL) at 0°C. was added a solution of sodium cyanate (0.743 g, 11.44 mmol, 2 eq.)in water (5.2 mL). The mixture was stirred at r.t. for 20 h. Water (100mL) was added and the reaction mixture turned into a suspension. After30 min, the solid was collected by filtration and the product cake waswashed with water (2×20 mL), dried in vacuum and purified by Biotage SP1Flash Purification System (eluent a gradient EA/MeOH, 100/0 to 90/10) toafford 288 as a white solid (2.0 g, 3.52 mmol, 62% yield). MS (m/z):568.4 (M+H).

Step 2:1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridine-7-yloxy)phenyl)urea(289)

To a solution of compound 288 (0.33 g, 0.581 mmol) in DCM (11.6 mL) wasadded TFA (0.53 mL, 6.98 mmol, 12 eq.). The reaction mixture was stirredat r.t. for 24 h, concentrated and the residue was purified by BiotageSP1 Flash Purification System (eluent a gradient DCM/MeOH/NH₄OH,95/5/0.1 to 9/1/0.2) to afford 289 as a white solid (0.256 g, 0.548mmol, 94% yield). Characterization of compound 289 is provided in theTable 6.

Example 191N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-phenyl-2-thioxoimidazolidine-1-carboxamide(303) Step 1. 1-phenylimidazolidine-2-thione (301)

1,1′-Thiocarbonyldiimidazole (4.51 g, 25.3 mmol) was added to a solutionof N-phenylethylenediamine (3 mL, 23.02 mmol) in THF (230 mL) and themixture was stirred for 2 h at room temperature. DCM was added and thesolution was washed with 1N HCl, dried over anhydrous sodium sulfate andconcentrated under reduced pressure affording title compound 301 (1.45g, 8.13 mmol, 35.3% yield). m/z: 179.1 (M+H)⁺

Step 2. tert-butyl(6-(7-(2-fluoro-4-(3-phenyl-2-thioxoimidazolidine-1-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(302)

Diphosgene (0.023 ml, 0.191 mmol) was added in one portion to a solutionof 126 (schemes 6 or 9) (0.200 g, 0.381 mmol) in THF (3.81 ml) and thereaction mixture stirred vigorously for 2 h.1-Phenylimidazolidine-2-thione (301, 0.102 g, 0.572 mmol) and sodiumhydride (60% in mineral oil) (0.046 g, 1.143 mmol) were addedsequentially and the mixture was stirred at room temperature for anadditional 1 h. The crude mixture was then suspended in EtOAc, washedwith water, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by preparative HPLC (column:Luna C18 (2), 5.0 cm ID; gradient: 80% MeOH to 95% MeOH in water, 60min) affording title compound 302 (0.068 g, 0.093 mmol, 24.5% yield) ascreamy solid. m/z: (M+1)⁺ 729.4 (100%).

Step 2.N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-phenyl-2-thioxoimidazolidine-1-carboxamide(303)

TFA (1 ml, 12.98 mmol) was added to a suspension of 302 (0.093 g, 0.128mmol) in DCM (1.000 ml) and the mixture was stirred at room temperaturefor 2 h. The reaction mixture was then concentrated under reducedpressure, the residue was dissolved in DCM, washed with 1N NaOHsolution, water, dried over anhydrous sodium sulfate and concentratedaffording title compound 303 (0.0714 g, 0.109 mmol, 85% yield) as whitesolid.

TABLE 6 Cpd. Ex. No. No. Structure Characterization 287 179

1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO- d6) δ(ppm): 8.75 (bs, 1H), 8.69 (bs, 1H), 8.13 (d, J = 5.48 Hz, 1H), 7.59 (s,1H), 7.32 (m, 1H), 6.96 (t, J = 9.19 Hz, 1H), 6.89 (s, 1H), 6.28 (m,1H), 6.28 (m, 2H), 3.92 (bs, 2H), 3.54 (s, 3H), 3.23 (t, J = 5.09 Hz,2H), 2.91 (s, 3H), 2.80 (m, 2H), 2.09 (m, 1H), 0.24 (m, 2H), 0.05 (m,2H). LRMS(ESI): (calc.) 510.58 (found) 511.4 (MH)+ 289 180

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO- d6) δ (ppm): 8.97(s, 1H); 8.68 (d, J = 1.6, 1H); 8.52 (d, J = 5.5, 1H); 8.39 (s, 1H);8.33 (d, J = 7.8, 1H); 8.02 (dd, J = 8.2, 2.2, 1H); 7.73 (dd, J = 14.2,2.3, 1H); 7.37 (t, J = 9.0, 1H); 7.17-7.15 (m, 1H); 6.65 (d, J = 4.5,1H); 6.05 (s, 2H); 4.14 (s, 2H); 3.54 (t, J = 5.1, 2H); 3.29 (s, 3H);3.03 (t, J = 5.1, 2H). LRMS(ESI): (calc.) 467.5 (found) 468.3 (MH)+

Other compounds according to the present invention are shown in Table 7.

TABLE 7 Cpd Ex. No. No. Structure Characterization 293 183

N1-(4-(2-(5-((2-(2-(2- Aminoethoxy)ethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N3-methyl-N3-phenylmalonamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 1H: 10.38(s, 1H); 8.57 (d, J = 1.6, 1H); 8.51 (d, J = 5.5, 1H); 8.37 (s, 1H);8.32 (s, 1H); 8.23 (d, J = 8.0, 1H); 7.89 (dd, J = 8.1, 2.1, 1H); 7.80(d, J = 13.2, 1H); 7.50-7.42 (m, 3H); 7.41-7.32 (m, 4H); 6.67 (d, J =5.3, 1H); 3.79 (s, 2H); 3.55- 3.47 (m, 8H); 3.23-3.21 (m, 5H); 2.83 (t,J = 5.5, 2H); 2.66 (t, J = 5.7, 2H). MS (M/Z): (calc.) 673.3 (found)673.4 294 184

1-(4-(2-(5-((2-(2-(2- Aminoethoxy)ethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 1H: 10.66(1H), 8.60 (s, 1H); 8.55-8.53 (m, 1H); 8.40-8.34 (m, 2H); 8.28-8.24 (m,1H); 7.93-7.90 (m, 1H); 7.82-7.78 (m, 1H); 7.45-7.35 (m, 2H); 6.70-6.68(m, 1H); 6.60-6.57 (m, 1H); 3.81 (s, 2H); 3.60-3.50 (m, 8H); 2.93-2.90(m, 2H); 2.70-2.65 (m, 2H); 2.37 (s, 3H). MS (M/Z): (calc.) 622.2(found) 622.4 298 188

1-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methylurea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 1H: 8.96 (s, 1H); 8.69 (d, J = 1.4, 1H); 8.53 (d, J = 5.3, 1H);8.40 (s, 1H); 8.34 (d, J = 8.2, 1H); 8.04 (dd, J = 8.2, 2.0, 1H); 7.72(dd, J = 13.7, 2.5, 1H); 7.37 (t, J = 9.2, 1H); 7.19-7.16 (m, 1H); 6.65(d, J = 5.4, 1H); 6.20 (q, J = 4.6, 1H); 4.18 (s, 1H); 3.56 (t, J = 5.3,1H); 3.30 (s, 3H); 3.10-3.06 (m, 2H); 2.66 (d, J = 4.5, 3H). MS: (calc.)482.2 (found) 482.3 (MH)+ 298a 188a

1-(2-chloro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(5- methylisoxazol-3-yl)urea¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.88 (s, 1H), 8.56 (s, 1H), 8.54 (d,1H, J = 5.3 Hz), 8.32 (s, 1H), 8.23 (m, 2H), 7.89 (d, 1H, J = 8.2 Hz),7.59 (d, 1H, J = 2.9 Hz), 7.31 (dd, 1H, J = 2.7 Hz, J = 8.8 Hz), 6.74(d, 1H, J = 5.3 Hz), 5.97 (s, 1H), 3.78 (s, 2H), 3.42 (s, 2H), 3.24 (s,3H), 2.65 (t, 2H, J = 5.7 Hz), 2.17 (s, 3H) MS: (calc.) 564.1 (found)565.3 (MH)+ 299 189

3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)biuret ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 1H: 8.58-8.56 (m, 2H); 8.36 (s, 1H); 8.25 (d, J = 8.0,1H); 7.90 (dd, J = 8.2, 1.8); 7.68 (q, J = 4.5, 2H); 7.59- 7.50 (m, 2H);7.22-7.18 (m, 1H); 6.84 (d, J = 5.3, 1H); 3.78 (s, 2H); 3.41 (t, J =5.7, 2H); 3.24 (s, 3H); 2.67 (d, J = 4.5, 6H); 2.65 (t, J = 5.7, 2H).MS: (calc.) 539.3 (found) 539.3 (MH)+

Other compounds according to the present invention are shown in Table 8.

TABLE 8 Cmpd. Ex. # # STRUCTURE CHARACTERIZATION 303 191

N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-phenyl-2- thioxoimidazolidine-1-carboxamide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.572 (s, 1H), 9.22 br, 2H), 8.75(d, J = 2.0 Hz, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.13 (dd, J = 2.1 Hz, J = 8.2 Hz, 1H), 7.84 (dd, J = 2.3Hz, J = 11.7 Hz, 1H), 7.55-7.50 (m, 4H), 7.42-7.38 (m, 2H), 6.75 (dd, J= 0.8 Hz, J = 4.7 Hz, 1H), 4.28-4.22 (m, 4H), 4.14-4.09 (m, 2H), 3.62(t, J = 4.9 Hz, 2H), 3.32 (s, 3H), 3.17 (m, 2H). MS (m/z): (M + 2)+ 2/2315.2 (73%), (M + 1)+ 629.4 (100%). 304 192

2-benzoyl-N-(4-(2-(5-((2-ethoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)hydrazinecarboxamide ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 10.36 (s, 1H), 9.42 (br, 1H), 8.63 (s, 1H), 8.53-8.48(m, 2H), 8.35 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.99-7.93 (m, 3H), 7.77(d, J = 13.7 Hz, 1H), 7.61-7.36 (m, 5H), 6.67 (d, J = 5.3 Hz, 1H), 3.94(s, 2H), 3.52-3.42 (m, 4H), 2.81 (m, 2H), 1.12 (t, J = 7.0 Hz, 3H). MS(m/z): (M + 2)+ 2/2 301.2 (100%), (M + 1)+ 601.4 (64%). 305 193

N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(4-fluorophenyl)-2-thioxoimidazolidine-1-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.52 (s, 1H), 8.57 (br, 1H), 8.53 (d, J = 5.4 Hz, 1H), 8.33 (s, 1H),8.24 (d, J = 8.0 Hz, 1H), 7.9 (d, J = 8.0 Hz, 1H), 7.8 (dd, J = 12.7 Hz,J = 1.7 Hz, 1H), 7.57-7.50 (m, 3H), 7.38-7.34 (m, 3H), 6.7 (d, J = 5.4Hz, 1H), 4.23 (dd, J = 8.7 Hz, J = 7.1 Hz, 1H), 4.09 (dd, J = 8.7 Hz, J= 7.1 Hz, 1H), 3.41 (t, J = 3.41 Hz, 2H), 3.17 (s, 1H), 4.09 (t, J =3.41 Hz, 2H). MS (m/z): (M + 2)+ 2/2 324.2 (73%), (M + 1)+ 647.4 (100%)306 194

N-(2-chloro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-phenyl-2- thioxoimidazolidine-1-carboxamide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.40 (s, 1H), 8.56- 8.54 (m, 2H),8.32-8.28 (m, 2H), 8.23 (d, J = 8.3 Hz, 1H), 1.89 (dd, J = 8.2 Hz, J =2.2 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.53-7.48 (m, 4H), 7.41-7.35 (m,2H), 6.77 (d, J = 2.5 Hz, 1H), 4.25 (m, 2H), 4.12 (m, 2H), 3.78 (s, 2H),5.49 (t, J = 5.49 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J = 5.49 Hz, 2H). MS(m/z): (M + 2)+ 2/2 323.1 (58%), 324 (39%); (M + 1)+ 645.4 (100%), 647.4(48%). 307 195

N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluorophenyl)-2-thioxoimidazolidine-1-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.39 (s, 1H), 8.78 (m, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H),8.23 (dd, J = 0.6 Hz, J = 8.2 Hz, 1H), 7.90 (dd, J = 2.1 Hz, J = 8.1 Hz,1H), 7.83 (dd, J = 2.6 Hz, J = 12.7 Hz, 1H), 7.60-7.49 (m, 3H),7.46-7.34 (m, 3H), 6.7 (dd, J = 0.9 Hz, J = 5.4 Hz, 1H), 4.31 (m, 2H),4.04 (m, 2H) 3.80 (s, 2H), 3.80 (s, 2H), 3.42 (t, J = 5.6 Hz, 2H), 3.25(s, 3H), 2.68 (t, J = 5.6 Hz, 2H). MS (m/z): (M + 2)+ 2/2 324.2 (89%),(M + 1)+ 647.4 (100%). 308 196

3-cyclopropyl-N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-thioxoimidazolidine-1- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.60 (s, 1H), 8.56 (m, 1H), 8.52 (d, J =5.6 Hz, 1H), 8.32 (s, 1H), 8.23 (dd, J = 8.2 Hz, J = 0.8 Hz, 1H), 7.89(dd, J = 7.7 Hz, J = 1.9 Hz, 1H), 7.80 (dd J = 12.8 Hz, 2.3 Hz, 1H),7.51 (t, J = 8.9 Hz, 1H), 7.36-7.33 (m, 1H), 6.99 (dd, J = 5.4 Hz, J=0.8 Hz, 1H), 4.02 (m, 2H), 3.77 (s, 2H), 3.61 (m, 2H), 3.41 (t, J = 5.7Hz, 2H), 3.24 (s, 3H), 3.06-3.02 (m, 1H), 2.64 (t, J = 5.7 Hz, 2H),0.87-0.84 (m 4H). MS (m/z): (M + 2)+ 2/2 297.2 (100%), (M + 1)+ 593.3(32%) 309 197

N-(4-(2-(5-((2-ethoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-phenyl-2-thioxoimidazolidine-1-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.57 (s, 1H), 8.57 (s, 1H), 8.53 (d, J = 5.3 Hz, 1H), 8.32 (s, 1H),8.24 (d, J = 7.5 Hz, 1H), 7.91-7.82 (m, 2H), 7.54- 7.51 (m, 5H),7.41-7.37 (m, 2H), 6.7 (d, J = 5.3 Hz, 1H), 4.24 (m, 2H), 4.11 (m, 2H),3.78 (s, 2H), 3.43 (q, J = 5.8 Hz, 2H), 3.39 (m, 2H), 2.65 (m, 2H), 1.11(t, J = 5.8 Hz, 3H). MS (m/z): (M + 2)+ 2/2 322.3 (89%), (M + 1)+ 643.4(100%). 310 198

3-benzyl-N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-thioxoimidazolidine-1- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.5 (s, 1H), 8.57 (dd, J = 0.7 Hz, J = 2.1Hz, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.23 (dd, J = 0.7 Hz, J= 8.2 Hz, 1H), 7.89 (dd, J = 2.2 Hz, J = 8.2 Hz, 1H), 7.82 (dd, J = 2.5Hz, J = 12.7 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 7.42-7.32 (m, 6H), 6.70(dd, J = 0.7 Hz J =5.5 Hz, 1H), 4.89 (s, 2H), 4.09 (m, 2H), 3.78 (s,2H), 3.64 (m, 2H), 3.41 (t, H = 5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J =5.7 Hz, 2H). MS (m/z): (M + 2)+ 2/2 322.3 (100%), (M + 1)+ 643.4 (51%).311 199

N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-propyl-2-thioxoimidazolidine- 1-carboxamide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.52 (s, 1H), 8.57 (dd, J = 0.7 Hz,J = 2.0 Hz, 1H), 8.53 (d, J = 5.4 Hz, 1H), 8.33 (s, 1H), 8.23 (dd, J =0.7 Hz, J = 8.1 Hz, 1H), 7.90 (dd, 2.1 Hz, 8.2 Hz, 1H), 7.81 (dd, J =2.6 Hz, J = 12.7 Hz, 1H), 7.51 (t, J = 9.2 Hz, 1H), 7.37-7.34 (m, 1H),6.69 (dd, J = 0.8 Hz, J = 5.4 Hz, 1H), 4.07 (m, 2H), 3.78 (s, 2H), 3.73(m, 2H), 3.58 (m, 2H), 3.41 (t, J = 5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t,J = 5.7 Hz, 2H), 1.66-1.61 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H). MS (m/z):(M + 2)+ 2/2 298.2 (100%), (M + 1)+ 595.4 (51%). 312 200

N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(3-fluorophenyl)-2-thioxoimidazolidine-1-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.48 (s, 1H), 8.57 (dd, J = 0.7 Hz, J = 2.2 Hz, 1H), 8.53 (d, J = 8.53Hz, 1H), 8.33 (s, 1H), 8.24 (dd, J = 0.7 Hz, J = 8.2 Hz, 1H), 7.90 (dd,J = 2.1 Hz, J = 8.2 Hz, 1H), 7.83 (dd, J = 2.5 Hz, J = 12.6 Hz, 1H),7.59-7.46 (m, 3H), 7.41-7.37 (m, 2H), 7.29-7.24 (m, 1H), 6.70 (dd, J =0.9 Hz, J = 5.5 Hz, 1H), 4.24 (m, 2H), 4.12 (m, 2H), 3.78 (s, 2H), 3.41(t, J = 5.7 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J = 5.7 Hz, 2H). MS (m/z):(M + 2)+ 2/2 324.2 (100%), (M + 1)+ 647.3 (46%). 313 201

N-(2,3-difluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-phenyl-2- thioxoimidazolidine-1-carboxamide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.62 (s, 1H), 8.57 (dd, J = 0.6 Hz,J = 2.0 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35 (s, 1H), 8.24 (d, J =8.2 Hz, 1H), 8.10-8.05 (m, 1H), 7.90 (dd, J = 2.2 Hz,J = 8.2 Hz, 1H),7.54- 7.51 (m, 4H), 7.44-7.38 (m, 2H), 6.83 (dd, J = 0.8 Hz, J = 5.5 Hz,1H), 4.28-4.24 (m, 2H), 4.15-4.01 (m, 2H), 3.79 (s, 2H), 3.41 (t, J =5.8 Hz, 2H), 3.24 (s, 3H), 2.66 (t, J = 5.8 Hz, 2H). MS (m/z): (M + 2)+2/2 324.2 (100%), (M + 1)+ 647.3 (55%)

Other compounds according to the present invention are shown in Table 9.

TABLE 9 Cpd. Ex. No. No. Structure Characterization 318 204

1-(3-fluoro-4-(2-(6-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO- d6) δ (ppm): 9.44(s, 1H), 8.49 (d, 1H, J = 5.5 Hz), 8.32 (s, 1H), 8.27 (br.s, 2H), 8.11(d, 1H, J = 6.2 Hz), 7.90 (t, 2H, J = 7.6 Hz), 7.73 (dd, 1H, J = 2.2 Hz,J = 13.7 Hz), 7.45 (d, 1H, J = 8.0 Hz), 7.33 (t, 1H, J = 9.0 Hz), 7.17(d, 1H, J = 9.0 Hz), 6.58 (d, 1H, J = 5.1 Hz), 6.17 (s, 2H), 3.89 (s,2H), 3.43 (s, 2H), 3.23 (s, 3H), 2.76 (br.s, 2H) LRMS(ESI): (calc.)467.1 (found) 468.3 (MH)+ 319 205

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)thiourea ¹H NMR (400 MHz, DMSO- d6) δ (ppm):9.96 (s, 1H); 8.56 (d, J = 1.6, 1H); 8.52 (d, J = 5.5, 1H); 8.32 (s,1H); 8.23 (d, J = 7.8, 1H); 7.89 (dd, J = 8.0, 2.0, 1H); 7.81 (dd, J =12.5, 2.0, 1H); 7.47 (t, J = 9.0, 1H); 7.29-7.26 (m, 1H); 6.67 (d, J =4.7, 1H); 3.77 (s, 2H); 3.40 (t, J = 5.7, 2H); 3.23 (s, 3H); 2.65 (t, J= 5.5, 2H). LRMS(ESI): (calc.) 483.1 (found) 484.3 (MH)+ 320 206

N-(3-fluoro-4-(2-(4-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide ¹H NMR(400 MHz, DMSO- d6) δ (ppm): 10.42 (s, 1H), 10.01 (s, 1H), 8.51 (d, J =5.6 Hz, 1H), 8.04 (s, 1H), 7.91 (dd, J = 2.4 and 13.6 Hz, 1H), 7.87-7.83(m, 2H), 7.65- 7.61 (m, 2H), 7.54-7.44 (m, 4H), 7.19-7.12 (m, 2H), 6.60(dd, J = 0.8 and 5.6 Hz, 1H), 3.81 (s, 2H), 3.42 (t, J = 5.6 Hz, 2H),3.25 (s, 3H), 2.70 (t, J = 5.6 Hz, 2H), 1.50- 1.43 (m, 4H). LRMS(ESI):(calc.) 628.2 (found) 629.5 (MH)+ 322 208

1-(3-fluoro-4-(2-(6-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5- (trifluoromethyl)phenyl)urea ¹HNMR (400 MHz, DMSO- d6) δ (ppm): 9.50 (s, 1H), 9.00 (d, 1H, J = 2.7 Hz),8.57 (dd, 1H, J = 2.2 Hz, J = 7.3 Hz), 8.51 (d, 1H, J =5.5 Hz), 8.34 (s,1H), 8.11 (d, 1H, J = 7.6 Hz), 7.89 (t, 1H, J = 7.8 Hz), 7.76 (dd, 1H, J= 2.6 Hz, J = 12.9 Hz), 7.4-7.6 (4H), 7.24 (m, 1H), 6.63 (d, 1H, J = 5.5Hz), 3.85 (s, 2H), 3.41 (t, 2H, J = 5.5 Hz), 3.22 (s, 3H), 2.71 (t, 2H,J = 5.5 Hz) LRMS(ESI): (calc.) 629.1 (found) 630.5 (MH)+ 329 215

1-cyclopropyl-3-(3-fluoro-4-(2-(6-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO- d6) δ (ppm): 8.18(d, 1H, J = 5.3 Hz0, 7.99 (s, 1H), 7.79 (d, 1H, J = 7.6 Hz), 7.59 (t,1H, J = 7.6 Hz), 7.37 (d, 1H, J = 15.3 Hz), 7.14 (d, 1H, J = 7.4 Hz),6.70 (t, 1H, J = 9.0 Hz), 6.61 (d, 1H, J = 8.8 Hz), 6.25 (d, 1H, J = 4.9Hz), 3.57 (d, 2H, J = 6.5 Hz), 2.94 (s, 3H), 2.43 (m, 2H), 2.03 (m, 1H),0.20 (d, 2H, J = 5.1 Hz), 0.00 (s, 2H). LRMS(ESI): (calc.) 507.2 (found)508.4 (MH)+ 332 218

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluorophenyl)urea ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.49 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.50 (d, 1H, J =5.4 Hz), 8.29 (s, 1H), 8.20 (d, 1H, J = 8.3 Hz), 8.09 (t, 1H, J = 8.2Hz), 7.87 (dd, 1H, J = 1.7 Hz, J = 8.0 Hz), 7.75 (dd, 1H, J = 2.6 Hz, J= 13.1 Hz), 7.44 (t, 1H, J = 9.0 Hz), 7.24 (m, 2H), 7.14 (t, 1H, J = 7.8Hz), 6.65 (d, 1H, J = 5.5 Hz), 3.75 (s, 2H), 3.38 (t, 2H, J = 5.7 Hz),3.21 (s, 3H), 2.62 (t, 2H, J = 5.7 Hz) LRMS(ESI): (calc.) 561.2 (found)562.5 (MH)+ 333 219

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzamide ¹H NMR (400 MHz, DMSO- d6) δ(ppm): 9.20 (s, 1H), 9.03 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.54 (d, J= 5.3 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.03-7.89 (m,3H), 7.78 (dd, J = 13.2, 2.4 Hz, 1H), 7.67-7.61 (m, 1H), 7.49 (d, J =8.8 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.36(bs, 1H), 7.32-7.26 (m, 1H), 6.69 (d, J = 5.3 Hz, 1H), 3.98 (bs, 2H),3.49 (t, J = 5.3 Hz, 2H), 3.27 (s, 3H), 2.92-2.83 (m, 2H), one NH ismissing (probably due to signal overlap with the solvent signals)LRMS(ESI): (calc.) 586.64 (found) 587.5 (MH)+ 336 222

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(3- (methylsulfonyl)phenyl)urea ¹H NMR (400MHz, DMSO- d6) δ (ppm): 9.29 (s, 1H), 9.21 (s, 1H), 8.57 (d, J = 1.8 Hz,1H), 8.53 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H),8.18 (t, J = 1.8 Hz, 1H), 7.90 (dd, J = 8.2, 2.0 Hz, 1H), 7.77 (dd, J =13.2, 2.4 Hz, 1H), 7.70 (dt, J = 7.8, 1.7 Hz, 1H), 7.62-7.52 (m, 2H),7.47 (t, J = 9.0 Hz, 1H), 7.31 (dd, J = 8.8, 1.6 Hz, 1H), 6.68 (d, J =5.5 Hz, 1H), 3.79 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 3.21(s, 3H), 2.66 (t, J = 5.7 Hz, 2H), one NH is missing (probably due tosignal overlap with the solvent signals) LRMS(ESI): (calc.) 621.7(found) 622.4 (MH)+ 337 223

1-(2,5-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO- d6) δ (ppm): 8.54(s, 1H), 8.50 (d, 1H, J = 5.3 Hz), 8.29 (s, 1H), 8.20 (d, 1H, J = 8.0Hz), 7.98 (m, 1H), 7.86 (d, 1H, J = 8.0 Hz), 7.74 (d, 1H, J = 13.1 Hz),7.43 (t, 1H, J = 9.0 Hz0, 7.25 (m, 2H), 6.82 (m, 1H), 6.64 (d, 1H, J =5.3 Hz), 3.75 (s, 2H), [3.34 (2H)], 3.21 (s, 3H), 2.62 (br.s, 2H), 2.22(br.s, 1H) LRMS(ESI): (calc.) 579.2 (found) 580.4 (MH)+ 338 224

(S)-N-(4-(7-(2-fluoro-4-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-N-(1-methoxypropan-2-yl)acetamide ¹H NMR (400 MHz, DMSO- d6) δ (ppm):mixture of rotamers, 9.64 (s, 1H), 9.18 (s, 1H), 8.54-8.48 (m, 1H), 8.06and 8.02 (2s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H),7.74 (dd, J = 13.0, 2.4 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.41 (d, J =8.4 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.28 (bd, J = 8.8 Hz, 1H), 6.62(t, J = 5.9 Hz, 1H), 6.58-6.52 (m, 1H), 4.74-4.16 (m, 3H), 3.42-3.23 (m,2H), 3.16 (s, 3H), 2.54-2.47 (m, 3H), 2.16 and 1.93 (2s, 3H), 1.09-1.00(m, 3H). LRMS(ESI): (calc.) 603.66 (found) 604.5 (MH)+ 339 225

N-((6-(7-(2-fluoro-4-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)acetamide ¹H NMR (400 MHz, DMSO- d6) δ(ppm): 9.66 (s, 1H); 9.23 (s, 1H); 8.50-8.45 (m, 2H); 8.32 (s, 0.3H);8.28 (s, 0.7H); 8.24 (d, J = 8.0, 0.3H); 8.18 (d, J = 8.0, 0.7H); 7.78-7.68 (m, 2H); 7.42 (t, J = 9.0, 1H); 7.25-7.21 (m, 1H); 6.64- 6.61 (m,1H); 6.51 (s, 1H); 4.67 (s, 0.6H); 4.54 (s, 1.4H); 3.50-3.40 (m, 4H);3.19 (s, 1.9H); 3.16 (s, 1.1H); 2.33 (s, 3H); 2.08 (s, 2.2H); 2.00 (s,0.8H) (2.3:1 mixture of rotamers) LRMS(ESI): (calc.) 591.2 (found) 591.3(MH)+ 340 226

N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)acetamide ¹H NMR (400 MHz, DMSO- d6) δ(ppm): 8.74 (s, 1H); 8.55-8.49 (m, 2H); 8.35 (s, 0.3H); 8.32 (s, 0.7H);8.28 (d, J = 8.6, 0.3H); 8.22 (d, J = 0.7H, 0.7H); 7.80-7.68 (m, 2H);7.38 (t, J = 9.0, 1H); 7.24-7.19 (m, 1H); 6.66-6.56 (m, 2H); 4.71 (s,0.6H); 4.59 (s, 1.4H); 3.53-3.41 (m, 4H); 3.24 (m, 2.2H); 3.20 (m,0.8H); 2.57- 2.50 (m, 1H); 2.13 (s, 2.2H); 2.05 (s, 0.8H); 0.67-0.63 (m,2H); 0.41-0.40 (m, 2H). (3:1 mixture of rotamers) LRMS(ESI): (calc.)550.2 (found) 550.5 (MH)+

Other compounds according to the present invention are shown in Table10.

TABLE 10 Cpd. Ex. No. No. Structure Characterization 341 227

1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea 342 228

N1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(2-fluorophenyl)malonamide 343 229

N¹-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide ¹H NMR (400 MHz, DMSO-d6) δ (ppm): LRMS(ESI):(calc.) 606.2 (found) 607.5 (MH)+ 344 230

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea 345 231

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluorophenyl)urea 346 232

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(4-fluorophenyl)urea 347 233

1-(2,5-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea 348 234

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluorophenyl)urea 349 235

1-(2,5-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

Other compounds according to the present invention are shown in Table11.

TABLE 11 Cpd. Ex. No. No. Structure Characterization 350 236

N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-(4- fluorophenyl)acetamide ¹H NMR(400 MHz, DMSO-d6) δ (ppm): 11.09 (s, 1H), 10.64 (s, 1H), 9.16 (s, 1H),8.72 (s, 1H), 8.58 (s, 1H), 8.43 (s, 1H), 8.38 (d, J = 8.0 Hz, 2H), 8.09(d, J = 7.6 Hz, 1H), 7.84 (d, J = 12.4 Hz, 1H), 7.51-7.42 (m, 2H),7.41-7.32 (m, 2H), 7.20- 7.15 (m, 2H), 6.72 (d, J = 4.8 Hz, 1H), 4.28(s, 2H), 4.8 Hz, 1H), 4.28 (s, 2H), 3.75 (s, 2H), 3.62-3.58 (m, 2H),3.31 (s, 3H), 3.22- 3.12 (m, 2H). LRMS(ESI): (calc.) 603.6 (found) 604.4(MH)+ 351 237

1-(3-fluoro-4-(2-(1-(3-(2- methoxyethylamino)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea ¹H NMR (400 MHz, DMSO-d6) δ(ppm): 9.72 (br, 1H), 9.41 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.73 (dd,J = 2.0 Hz, J = 12.9 Hz, 1H), 7.57 (d, H = 6.2 Hz, 1H), 7.44 (t, J = 8.9Hz, 1H), 7.27 (m, 1H), 6.62 (t, J = 4.5 Hz, 1H), 6.55 (d, J = 1 Hz, 1H),6.42 (m, 1H), 4.22-4.18 (m, 2H), 3.73-3.68 (m, 2H), 3.43-3.41 (m, 2H),3.25 (s, 3H), 2.85-2.78 (m, 2H), 2.70 (m, 1H), 2.67- 2.56 (m, 3H), 2.37(d, J = 0.8 Hz, 3H) LRMS(ESI): (calc.) 594.7 (found) 595.5 (MH)+ 352 238

1-cyclopropyl-3-(3-fluoro-4-(2-(1-(3-(2-methoxyethylamino)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)urea ¹H NMR(400 MHz, DMSO-d6) δ (ppm): 1H: 8.79 (br, 1H), 8.45 (d, J = 6.0 Hz, 1H),7.71 (dd, J = 2.3 Hz, J = 13.4 Hz, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.35(t, J = 9.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.63 (br, 1H), 6.58 (t, J= 4.5 Hz, 1H), 6.41 (m, 1H), 4.22-4.18 (m, 2H), 3.73-3.67 (m, 2H),3.42-3.39 (m, 2H), 3.24 (s, 3H), 2.84-2.81 (m, 2H), 2.76-2.74 (m, 2H),2.69 (m, 1H), 2.63-2.52 (m, 4H), 0.67-0.62 (m, 2H), 0.44-0.40 (m, 2H)LRMS(ESI): (calc.) 553.7 (found) 554.5 (MH)+ 353 239

1-(3-fluoro-4-(2-(1-(3-(2- methoxyethylamino)propanoyl)-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5- (trifluoromethyl)phenyl)urea ¹H NMR (400MHz, DMSO-d6) δ (ppm): 10.08 (br, 1H), 9.24 (br, 1H), 8.59 (dd, J = 2.3Hz, J = 7.3 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H),7.77 (dd, J = 2.2 Hz, J = 13.0 Hz, 1H), 7.58 (d, J = 3.4 Hz, 1H),7.54-7.41 (m, 3H), 7.27 (d, J = 10.1 Hz, 1H), 6.64 (t, J = 5.0 Hz, 1H),6.43 (m, 1H), 4.20 (m, 2H), 3.75- 3.67 (m, 2H), 3.55-3.52 (m, 2H), 3.28(s, 3H), 3.07- 3.01 (m, 4H), 2.81-2.72 (m, 3H), 2.62 (m, 1H) LRMS(ESI):(calc.) 675.7 (found) 676.5 (MH)+ 354 240

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(pyridin-3-yl)urea ¹H NMR (400 MHz, DMSO-d6)δ (ppm): 9.24 (s, 1H), 9.03 (s, 1H), 8.58 (d, 1H, J = 2.0 Hz), 8.53 (d,1H, J = 1.6 Hz), 8.48 (d, 1H, J = 5.5 Hz), 8.27 (s, 1H), 8.18 (d, 1H, J= 8.2 Hz), 8.10 (m, 1H), 7.91 (m, 1H), 7.85 (dd, 1H, J = 2.2 Hz, J =8.0), 7.71 (dd, 1H, J = 2.5 Hz, J = 13.3 Hz), 7.41 (t, 1H, J = 9.0 Hz),7.30 (dd, J = 5.1 Hz, J = 8.2 Hz), 7.25 (m, 1H), 6.63 (d, 1H, J = 5.1Hz), 3.73 (s, 2H), [3.3 2H], 3.19 (s, 3H), 2.60 (t, 2H, J = 5.7 Hz)LRMS(ESI): (calc.) 544.2 (found) 545.5 (MH)+ 355 241

N-((6-(7-(2-fluoro-4-(3-(2-fluoro-5-(trifluoromethyl)phenyl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2- methoxyethyl)acetamide ¹H NMR(400 MHz, DMSO-d6) δ (ppm): mixture of rotamers; 9.52 (s, 1H), 9.02 and9.01 (2s, 1H), 8.59 (dd, J = 7.2, 2.0 Hz, 1H), 8.56-8.49 (m, 2H), 8.37and 8.34 (2s, 1H), 8.29 and 8.23 (2d, J = 8.0 Hz, 1H), 7.82-7.74 (m,2H), 7.56-7.40 (m, 3H), 7.30-7.24 (m, 1H), 6.71- 6.66 (m, 1H), 4.71 and4.59 (2s, 2H), 3.53-3.38 (m, 4H), 3.24 and 3.21 (2s, 3H), 2.13 and 2.05(2s, 3H). LRMS(ESI): (calc.) 671.16 (found) 672.5 (MH)+ 356 242

1-(3-fluoro-4-(2-(4-((methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5- (trifluoromethyl)phenyl)urea ¹H NMR (400MHz, DMSO-d6) δ (ppm): 9.49 (s, 1H), 8.98 (s, d, 1H, J = 2.4 Hz), 8.56(dd, 1H, J1 = 7.0 Hz, J2 = 2.0 Hz), 8.48 (d, 1H, 7.81 (d, 2H, J = 8.2Hz), J = 5.5 Hz), 8.00 (s, 1H), 7.81 (d, 2H, J = 8.2 Hz), 7.74 (dd, J1 =2.4 Hz, J2 = 12.9 Hz), 7.49-7.39 (m, 5H), 7.23 (d, 1H, J = 9.0 Hz), 6.59(d, 1H, J = 5.5 Hz), 3.50 (s, 2H), 2.50-2.28 (m, 12H), 2.13 (s, 3H),2.11 (s, 3H). LRMS(ESI): (calc.) 710.2 (found) 711.5 (MH)+ 357 243

1-cyclopentyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.61(s, 1H), 8.53 (d, 1H, J = 1.6 Hz), 8.47 (d, 1H, J = 5.3 Hz), 8.27 (s,1H), 8.18 (d, 1H, J = 8.2 Hz), 7.85 (dd, 1H, J = 2.1 Hz, J = 8.2 Hz),7.67 (dd, 1H, J = 2.6 Hz, J = 13.5 Hz), 7.32 (t, 1H, J = 9.0 Hz), 7.09(m, 1H), 6.59 (d, 1H, J = 5.4 Hz), 6.28 (d, 1H, J = 7.1 Hz) LRMS(ESI):(calc.) 535.2 (found) 536.4 (MH)+ 358 244

1-(cyclopropylmethyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO-d6) δ (ppm):DMSO-d69.20 (s, 1H), 8.39 (s, 1H), 8.33 (d, 1H, J = 5.3 Hz), 8.12 (s,1H), 8.04 (d, 1H, J = 8.2 Hz), 7.71 (dd, 1H, J = 1.7 Hz, J = 8.2 Hz),7.55 (dd, 1H, J = 2.2 Hz, J = 13.7 Hz), 7.17 (t, 1H, J = 9.2 Hz), 7.00(d, 1H, J = 8.6 Hz), 6.70 (m, 1H), 6.45 (d, 1H, J = 5.4 Hz), 3.59 (s,2H), 3.22 (t, 2H, 5.7 Hz), 3.05 (s, 3H), 2.79 (t, 2H, J = 6.2 Hz), 1.54(s, 1H), 0.76 (m, 1H), 0.23 (m, 2H), 0.01 (m, 2H) LRMS(ESI): (calc.)521.2 (found) 522.4 (MH)+ 359 245

1-(2,4-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO-d6)δ (ppm): 10.90 (s, 1H), 8.89 (s, 1H), 8.50 (d, J = 5.48 Hz, 1H), 7.98(m, 1H), 7.95 (s, 1H), 7.72 (m, 1H), 7.41 (m, 1H), 7.28- 7.20 (m, 3H),7.04 (m, 1H), 4.28 (s, 2H), 3.92 (s, 3H), 3.61 (m, 2H), 3.27 (s, 3H),3.13 (m, 2H) LRMS(ESI): (calc.) 582.60 (found) 583.5 (MH)+ 360 246

1-benzyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 9.0 (s,1H), 8.57 (d, J = 1.4 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H),8.23 (d, J = 8.5 Hz, 1H), 7.89 (dd, J = 1.8 Hz, J = 8.1 Hz, 1H), 7.73(dd, J = 2.6 Hz, J = 13.5 Hz, 1H), 7.41-7.24 (m, 5H), 7.24- 7.18 (m,2H), 6.82-6.79 (m, 1H), 5.28 (d, J = 5.28 Hz, 1H), 4.32 (d, J = 6.4 Hz,2H), 3.78 (s, 2H), 3.41 (t, J = 5.8 Hz, 2H), 3.26 (s, 3H), 2.65 (t, J =5.8 Hz, 2H) LRMS(ESI): (calc.) 557.6 (found) 558.5 (MH)+ 361 247

benzyl 3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate ¹H NMR (400 MHz, DMSO-d6) δ (ppm):10.2 (s, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.32(s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.90 (dd, J = 1.9 Hz, J = 8.1 Hz,1H), 7.66 (dd, J = 8.3 Hz, J = 8.1 Hz, 1H), 7.49-7.33 (m, 7H), 6.65 (dd,J = 0.6 Hz, J = 5.5 Hz, 1H), 5.19 (s, 2H), 3.79 (s, 2H), 3.41 (t, J =5.7 Hz, 2H), 3.24 (s, 3H), 2.66 (t, J = 5.7 Hz, 2H) LRMS(ESI): (calc.)558.6 (found) 559.4 (MH)+ 362 248

1-(cyclohexylmethyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO-d6) δ (ppm): DMSO-d68.80 (s, 1H), 8.51 (s, 1H), 8.46 (d, 1H, J = 5.3 Hz), 8.26 (s, 1H), 8.17(d, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 7.9 Hz), 7.67 (d, 1H, J = 13.5Hz), 7.31 (t, 1H, J = 9.0 Hz), 7.09 (d, 1H, J = 8.4 Hz), 6.58 (d, 1H, J= 5.0 Hz), 6.33 (m, 1H), 3.72 (s, 2H), 3.35 (t, Hz), 2.59 (t, 2H, J =5.3 Hz0, 1.62 (m, 5H), 1.34 (m, 1H), 1.11 (m, 3H), 0.86 (m, 2H)LRMS(ESI): (calc.) 563.2 (found) 564.5 (MH)+

Other compounds according to the present invention are shown in Table12.

TABLE 12 Cpd. Ex. No. No. Structure 363 249

3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-(2-fluoro-5-(trifluoromethyl)phenyl)-1-methylurea 364 250

1-cyclopentyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea 365 251

1-(3-acetylphenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea 366 252

1-cyclopropyl-3-(3-fluoro-4-(2-(4-((methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea 367 253

benzyl (2-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate

Other compounds according to the present invention are shown in Table13.

TABLE 13 Cpd. Ex. No. No. Structure Characterization 368 254

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 9.27 (s, 1 H), 9.11 (s, 1 H), 8.48(d, J = 5.48 Hz, 1 H), 7.87 (s, 1 H), 7.70 (m, 1 H), 7.46 (d, J = 9 Hz,2 H), 7.41 (t, J = 7.82 Hz, 1 H), 7.30 (d, J = 8.80 Hz, 2 H), 7.21 (m, 1H), 6.95 (s, 1 H), 6.65 (d, J = 5.28 H, 1 H), 3.88 (s, 3 H), 3.79 (s, 2H), 3.39 (m, 2 H), 3.21 (s, 3 H), 2.71 (m, 2 H) LRMS (ESI): (calc.)581.06 (found) 581.4 (MH)+ 369 255

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 10.56 (s, 1 H), 8.56 (d, J = 2.2 Hz,1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.32 (s, 1 H), 8.23 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.0, 2.0 Hz, 1 H), 7.85 (dd, J = 12.9, 2.3 Hz, 1 H),7.69-7.61 (m, 2 H), 7.50 (t, J = 8.7 Hz, 1 H), 7.44 (dd, J = 9.0, 2.3Hz, 1 H), 7.33-7.24 (m, 2 H), 6.68 (d, J = 5.3 Hz, 1 H), 3.96 (bs, 4 H),3.78 (s, 2 H), one CH2 is masked by water, 3.33 (s, 3 H), 2.65 (t, J =5.7 Hz, 2 H), one NH is missing. LRMS (ESI): (calc.) 630.66 (found)631.5 (MH)+ 370 256

¹H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 10.56 (s, 1 H),8.58-8.46 (m, 2 H), 8.40-8.20 (m, 2 H), 7.90-7.74 (m, 2 H), 7.70-7.60(m, 2 H), 7.55-7.42 (m, 2 H), 7.29 (t, J = 8.9 Hz, 2 H), 6.73-6.66 (m, 1H), 4.71 and 4.59 (2 s, 2 H), 3.96 (bs, 4 H), 3.54-3.40 (m, 4 H), 3.24and 3.20 (2 s, 3 H), 2.13 and 2.05 (2 s, 3 H). LRMS (ESI): (calc.) 672.7(found) 673.3 (MH)+ 371 257

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 9.12 (s, 1 H), 0.02 (s, 1 H), 8.48(d, J = 5.48 Hz, 1 H), 7.85 (s, 1 H), 7.70 (m, 1 H), 7.53 (d, J = 9.19Hz, 2 H), 7.41 (t, J = 8.99 Hz, 1 H), 7.27 (m, 3 H), 6.92 (s, 1 H), 6.65(d, J = 5.28 Hz, 1 H), 3.87 (s, 3 H) (, 3.73 (s, 2 H), 3.34 (m, 2 H),3.20 (s, 3 H), 2.62 (t, J = 5.67 Hz, 2 H). LRMS (ESI): (calc.) 630.6(found) 632.5 (MH)+

Pharmaceutical Compositions

In one embodiment, the invention provides pharmaceutical compositionscomprising a compound according to the invention and a pharmaceuticallyacceptable carrier, excipient, or diluent. Compositions of the inventionmay be formulated by any method well known in the art and may beprepared for administration by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain embodiments, compositions ofthe invention are administered intravenously in a hospital setting. Incertain other embodiments, administration may be by, for example, theoral route.

The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term “pharmaceutically acceptable salt(s)” refers tosalts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to, salts formed with inorganic acids (for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, andthe like), and salts formed with organic acids such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamicacid, naphthalenesulfonic acid, naphthalenedisulfonic acid,methanesulfonic acid, p-toluenesulfonic acid and polygalacturonic acid.The compounds can also be administered as pharmaceutically acceptablequaternary salts known by those skilled in the art, which specificallyinclude the quaternary ammonium salt of the formula —NR+Z—, wherein R ishydrogen, alkyl, or benzyl, and Z is a counterion, including chloride,bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate,phosphate, or carboxylate (such as benzoate, succinate, acetate,glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate,cinnamoate, mandeloate, benzyloate, and diphenylacetate).

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated. The effective dosage range of thepharmaceutically acceptable derivatives can be calculated based on theweight of the parent compound to be delivered. If the derivativeexhibits activity in itself, the effective dosage can be estimated asabove using the weight of the derivative, or by other means known tothose skilled in the art.

Inhibition of VEGF Receptor Signaling and HGF Receptor Signaling

In another embodiment the invention provides a method of inhibiting VEGFreceptor signaling and HGF receptor signaling in a cell, comprisingcontacting a cell in which inhibition of VEGF receptor signaling and HGFreceptor signaling is desired with an inhibitor of VEGF receptorsignaling and HGF receptor signaling according to the invention. Becausecompounds of the invention inhibit VEGF receptor signaling and HGFreceptor signaling, they are useful research tools for in vitro study ofthe role of VEGF receptor signaling and HGF receptor signaling inbiological processes. In one example of this embodiment, the methodcauses an inhibition of cell proliferation of the contacted cells.

ASSAY EXAMPLES Inhibition of c-Met and VEGF Activity

The following protocols were used to assay the compounds of theinvention.

Assay Example 1 In Vitro Receptor Tyrosine Kinase Assays (c-Met/HGFReceptor and VEGF Receptor KDR)

These tests measure the ability of compounds to inhibit the enzymaticactivity of recombinant human c-Met/HGF receptor and VEGF receptorenzymatic activity.

A 1.3-kb cDNA corresponding to the intracellular domain of c-Met orc-Met IC (Genbank accession number NP000236-1 amino acid 1078 to 1337)is cloned into the BamHI/XhoI sites of the pBlueBacHis2A vector(Invitrogen) for the production of a histidine-tagged version of thatenzyme. This construct is used to generate recombinant baculovirus usingthe Bac-N-Blue™ system according to the manufacturer's instructions(Invitrogen).

The c-Met IC protein is expressed in Hi-5 cells (Trichoplusia Ni) uponinfection with recombinant baculovirus construct. Briefly, Hi-5 cellsgrown in suspension and maintained in serum-free medium (Sf900 IIsupplemented with gentamycin) at a cell density of about 2×10⁶ cells/mlare infected with the above-mentioned viruses at a multiplicity ofinfection (MOI) of 0.2 during 72 hours at 27° C. with agitation at 120rpm on a rotary shaker. Infected cells are harvested by centrifugationat 398 g for 15 min. Cell pellets are frozen at −80° C. untilpurification is performed.

All steps described in cell extraction and purification are performed at4° C. Frozen Hi-5 cell pellets infected with the C-Met IC recombinantbaculovirus are thawed and gently resuspended in Buffer A (20 mM Tris pH8.0, 10% glycerol, 1 g/ml pepstatin, 2 μg/ml Aprotinin and leupeptin, 50μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64, 0.5 mM DTT and 1 mM Levamisole)using 3 ml of buffer per gram of cells. The suspension is Douncehomogenized after which it is centrifuged at 22500 g, 30 min., 4° C. Thesupernatant (cell extract) is used as starting material for purificationof c-Met IC.

The supernatant is loaded onto a QsepharoseFF column (AmershamBiosciences) equilibrated with Buffer B (20 mM Tris pH 8.0, 10%glycerol) supplemented with 0.05M NaCl. Following a ten column volume(CV) wash with equilibration buffer, bound proteins are eluted with a 5CV salt linear gradient spanning from 0.05 to 1M NaCl in Buffer B.Typically, the conductivity of selected fractions rank between 6.5 and37 mS/cm. This Qsepharose eluate has an estimated NaCl concentration of0.33M and is supplemented with a 5M NaCl solution in order to increaseNaCl concentration at 0.5M and also with a 5M Imidazole (pH 8.0)solution to achieve a final imidazole concentration of 15 mM. Thismaterial is loaded onto a HisTrap affinity column (GE Healthcare)equilibrated with Buffer C (50 mM NaPO4 pH 8.0, 0.5M NaCl, 10% glycerol)supplemented with 15 mM imidazole. After a 10 CV wash with equilibrationbuffer and an 8 CV wash with buffer C+40 mM imidazole, bound proteinsare eluted with an 8 CV linear gradient (15 to 500 mM) of imidazole inbuffer C. C-Met IC enriched fractions from this chromatography step arepooled based on SDS-PAGE analysis. This pool of enzyme undergoes bufferexchange using PD-10 column (GE Healthcare) against buffer D (25 mMHEPES pH 7.5, 0.1M NaCl, 10% glycerol and 2 mM β-mercaptoethanol). FinalC-Met IC protein preparations concentrations are about 0.5 mg/ml withpurity approximating 80%. Purified c-Met IC protein stocks aresupplemented with BSA at 1 mg/ml, aliquoted and frozen at −80° C. priorto use in enzymatic assay.

In the case of VEGF receptor KDR a 1.6-kb cDNA corresponding to thecatalytic domain of VEGFR2 or KDR (Genbank accession number AF035121amino acid 806 to 1356) is cloned into the Pst I site of the pDEST20Gateway vector (Invitrogen) for the production of a GST-tagged versionof that enzyme. This construct is used to generate recombinantbaculovirus using the Bac-to-Bac™ system according to the manufacturer'sinstructions (Invitrogen).

The GST-VEGFR2806-1356 protein is expressed in Sf9 cells (Spodopterafrugiperda) upon infection with recombinant baculovirus construct.Briefly, Sf9 cells grown in suspension and maintained in serum-freemedium (Sf900 II supplemented with gentamycin) at a cell density ofabout 2×10⁶ cells/ml are infected with the above-mentioned viruses at amultiplicity of infection (MOI) of 0.1 during 72 hours at 27° C. withagitation at 120 rpm on a rotary shaker. Infected cells are harvested bycentrifugation at 398 g for 15 min. Cell pellets are frozen at −80° C.until purification is performed.

All steps described in cell extraction and purification are performed at4° C. Frozen Sf9 cell pellets infected with the GST-VEGFR2806-1356recombinant baculovirus are thawed and gently resuspended in Buffer A(PBS pH 7.3 supplemented with 1 μg/ml pepstatin, 2 μg/ml Aprotinin andleupeptin, 50 μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64 and 0.5 mM DTT)using 3 ml of buffer per gram of cells. Suspension is Dounce homogenizedand 1% Triton X-100 is added to the homogenate after which it iscentrifuged at 22500 g, 30 min., 4° C. The supernatant (cell extract) isused as starting material for purification of GST-VEGFR2806-1356.

The supernatant is loaded onto a GST-agarose column (Sigma) equilibratedwith PBS pH 7.3. Following a four column volume (CV) wash with PBS pH7.3+1% Triton X-100 and 4 CV wash with buffer B (50 mM Tris pH 8.0, 20%glycerol and 100 mM NaCl), bound proteins are step eluted with 5 CV ofbuffer B supplemented with 5 mM DTT and 15 mM glutathion.GST-VEGFR2806-1356 enriched fractions from this chromatography step arepooled based on U.V. trace i.e. fractions with high O.D.280. FinalGST-VEGFR2806-1356 protein preparations concentrations are about 0.7mg/ml with purity approximating 70%. Purified GST-VEGFR2806-1356 proteinstocks are aliquoted and frozen at −80° C. prior to use in enzymaticassay.

Inhibition of c-Met/HGF receptor and VEGFR/KDR is measured in a DELFIA™assay (Perkin Elmer). The substrate poly(Glu4,Tyr) is immobilized ontoblack high-binding polystyrene 96-well plates. The coated plates arewashed and stored at 4° C. During the assay, enzymes are pre-incubatedwith inhibitor and Mg-ATP on ice in polypropylene 96-well plates for 4minutes, and then transferred to the coated plates. The subsequentkinase reaction takes place at 30° C. for 10-30 minutes. ATPconcentrations in the assay are 10 uM for C-Met (5× the Km) and 0.6 uMfor VEGFR/KDR (2× the Km). Enzyme concentration is 25 nM (C-Met) or 5 nM(VEGFR/KDR). After incubation, the kinase reactions are quenched withEDTA and the plates are washed. Phosphorylated product is detected byincubation with Europium-labeled anti-phosphotyrosine MoAb. Afterwashing the plates, bound MoAb is detected by time-resolved fluorescencein a Gemini SpectraMax reader (Molecular Devices). Compounds areevaluated over a range of concentrations and IC₅₀'s (concentration ofcompounds giving 50% inhibition of enzymatic activity) are determined.The results are shown in Table 2, columns B and C

Assay Example 2 Inhibition of c-Met Phosphorylation in MKN45 Cells

The following assay is used to determine inhibition of c-Metphosphorylation.

The c-Met receptor is expressed in numerous cancer cell lines derivedfrom tumors of epithelial origin. In MKN45 gastric carcinoma cells thec-Met gene is amplified, resulting in several-fold overexpression of thereceptor and its constitutive activation. For this reason constitutivelyhigh levels of ERK1/2 are also detected in these cells, independently ofHGF-added stimulation (Smolen G A, Sordella R, Muir B, Mohapatra G,Barmettler A, Archibald H, et al. Amplification of MET may identify asubset of cancers with extreme sensitivity to the selective tyrosinekinase inhibitor PHA-665752. Proc Natl Acad Sci USA 2006). We havedeveloped a sensitive method to follow c-Met phosphorylation in thesecells. In previous studies with earlier generation c-Met inhibitors, weestablished that the IC₅₀s for the inhibition of c-Met phosphorylationwere identical using this novel ELISA approach and standard western blotprocedure, with antibodies directed against the activating autocatalysistyrosine residues of c-MET (Tyr Y1230-34-35).

Cell treatments: MKN45 cells are seeded into wells of 96-well plates ata density of 3×10⁴ cells/well in RPMI medium supplemented with 10% FBS.HA-TPR-RON expressing 293T (clone 18) cells are seeded into wells of96-well plates at a density of 3×10⁴ cells/well in DMEM mediumsupplemented with 10% FBS. Cells are grown for 48 h prior to treatmentswith compounds of interest. Inhibitors are added to the medium intriplicate wells at the indicated doses. After 3 h of treatment, mediais aspirated and cells are lysed by one freeze-thaw cycle in 50 μL/wellhypotonic lysis buffer (25 mM HEPES pH 7.5, 10 mM NaCl with 1 mM4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride, 200 μM sodiumorthovanadate, 1 mM sodium fluoride, 10 μg/mL of leupeptin, 10 μg/mL ofaprotinin/mL, 1 μg/mL of pepstatin and 50 μg/mL Na-p-tosyl-L-lysinechloromethyl ketone hydrochloride.

Detection of phosphorylated c-Met by direct ELISA: Lysate samples (5 μL)from wells of treatment plates are transferred to 80 μL of bindingbuffer (25 mM HEPES pH 7.5, 200 mM NaCl) in wells of high binding whitepolysterene 96-well plates (Corning). After an overnight protein bindingincubation at 4° C., lysates are aspirated and wells are blocked for 1 hat 37° C. in TBST supplemented with 5% BSA. Plates are incubated withthe primary antibodies anti-phospho-Tyrosine (Millipore, 4G10) diluted1/15000 in TBST supplemented with 5% BSA for 1 h at room temperature.Plates are washed 3 times on a plate washer (SkanWasher, MolecularDevises), and incubated with the reporter antibodyanti-rabbit-horseradish peroxidase (Sigma) diluted 1/15000 in TBSTsupplemented with 5% BSA, for 1 h at room temperature. Plates are washed3 times with TBST using on a plate washer and subsequently incubatedwith chemiluminescent substrate solution (ECL, Roche). Luminescencesignal is captured on a Polar Star Optima apparatus (BMG LabTech).

Average values of the triplicate samples are used to prepare IC₅₀ curvesusing a 4-parameter fit model. These curves are calculated using, forexample, GraFit 5.0 software. For assay standardization purpose, aninternal control is included on each experimental test plate. Theresults are shown in Table 2, column F.

Assay Example 3 Inhibition of c-MET Dependent Motiliy

Activation of the c-Met receptor by its ligand HGF induces signaltransduction pathways implicated in the regulation of cell migration Theprostate carcinoma cells DU145 have been shown to express high levels ofthe c-Met receptor and respond to HGF in cell based assays by cellscattering (Miura H, Nishimura K, Tsujimura A, Matsumiya K, Matsumoto K,Nakamura T, et al. Effects of hepatocyte growth factor onE-cadherin-mediated cell-cell adhesion in DU145 prostate cancer cells.Urology 2001; 58(6):1064-9). The A549 cells are lung carcinoma cellsthat have also been shown to express high levels of c-Met, and exhibitmotility upon stimulation with HGF in the context of wound healing cellbased assays (Nakamura T, Matsumoto K, Kiritoshi A, Tano Y, Nakamura T.Induction of hepatocyte growth factor in fibroblasts by tumor-derivedfactors affects invasive growth of tumor cells: in vitro analysis oftumor-stromal interactions. Cancer Res 1997; 57(15):3305-13).

Scatter assays in DU145. The scatter assay is performed as describedpreviously (Miura H, Nishimura K, Tsujimura A, Matsumiya K, Matsumoto K,Nakamura T, et al. Effects of hepatocyte growth factor onE-cadherin-mediated cell-cell adhesion in DU145 prostate cancer cells.Urology 2001; 58(6):1064-9) for DU145 prostate carcinoma cells with theindicated modifications. In brief, DU145 cells (ATCC) are seeded in24-well plates at a density of 7×10³ cells/well in MEM mediumcomplemented with 10% FBS and cultured for 48 h, to allow the formationof small compact colonies of cells. Inhibitors are subsequently added ata range of doses (0.00032-10 uM) for 3 h. Cells are then stimulated tomigrate by the addition of HGF (in the form of conditioned medium from293T cells over-expressing the human HGF gene) and the culture iscontinued for another 24 h. The IC₅₀ values is defined as the last dosethat created an inhibitory effect on scattering. For the purpose ofstandardization a control is carried on every test plates for the DU145scattering assays. The results are shown in Table 2, column E.

Wound healing assay in A549 cells. A549 cells (ATCC) are seeded in DMEMlow glucose medium complemented with 10% FBS into 24-well plates at adensity of 7.5×10⁴ cells/well and grown to confluence (48 h). Inhibitorswere added to the medium at a range of doses (0.00032-10 uM) for 3 h atwhich point a gap is introduced by scraping cells with a P1000 pipettetip. Cells are then stimulated to migrate by the addition of HGF (in theform of conditioned medium from 293T cells over-expressing the human HGFgene) and the culture is continued for 24 h. The IC₅₀ values are definedas the last dose that inhibited gap closing by more than 25%. For thepurpose of standardization, a control is carried on every assay plates.The results are shown in Table 2, column D.

Biological Assay Results

The activities of some of the compounds according to the inventionmeasured by the above assays are displayed in Table 2. In the table, “a”indicates inhibitory activity at a concentration of less than 250nanomolar; “b” indicates inhibitory activity at a concentration ≧250 but<500 nanomolar, “c” indicates inhibitory activity at ≧500 but <1000nanomolar; and “d” indicates inhibitory activity ≧1000 nanomolar.

TABLE 2 D A549 B C WOUND_(—) CMET VEGFR HEALING A IC50 IC50 IC50Structure (μM) (μM) (μM)

a a b

a a b

a b d

a a b

a a d

a a b

a a b

a a d

a a b

a a b

a a b

a a b

a b b

a a b

a a a

a a b

a a b

a a b

a a b

a a d

a a c

a a d

a a b

a a d

a a a

a a b

a a d

a a b

a a d

a a d

a a b

a a a

a a b

a a a

a a a

a a a

a a a

a a b

a a a

a a a

a a d

a a b

a a b

a a a

a a a

a a b

a a a

a a a

a a a

a a b

a a b

a a b

a a b

a a a

a a a

a a a

a a b

a a a

a a a

a

a a

d B

b b

b a F E CMET DU145 ELISA SCATT. IN INHIB MKN45 A IC50 IC50 Structure(μM) (μM)

b a

a a

b b

b a

d a

b a

b b

d a

b a

b a

b a

b a

b a

a a

a a

b a

b c

d a

b b

b a

d c

b a

b a

d a

a a

b a

b a

b a

b a

b a

b a

a a

a a

a a

a a

a a

a a

b b

b a

a a

b a

b a

a a

a a

a a

a a

a a

a a

a a

b a

b a

b a

b b

a a

a a

a a

b a

b a

a A

Assay Example 4 In Vivo Solid Tumor Disease Model

This test measures the capacity of compounds to inhibit solid tumorgrowth.

Tumor xenografts are established in the flank of female athymic CD1 mice(Charles River Inc.), by subcutaneous injection of 1×106 U87, A431 orSKLMS cells/mouse. Once established, tumors are then serially passageds.c. in nude mice hosts. Tumor fragments from these host animals areused in subsequent compound evaluation experiments. For compoundevaluation experiments female nude mice weighing approximately 20 g areimplanted s.c. by surgical implantation with tumor fragments of ˜30 mgfrom donor tumors. When the tumors are approximately 100 mm3 in size(˜7-10 days following implantation), the animals are randomized andseparated into treatment and control groups. Each group contains 6-8tumor-bearing mice, each of which is ear-tagged and followedindividually throughout the experiment.

Mice are weighed and tumor measurements are taken by calipers threetimes weekly, starting on Day 1. These tumor measurements are convertedto tumor volume by the well-known formula (L+W/4)3 4/3π. The experimentis terminated when the control tumors reach a size of approximately 1500mm³. In this model, the change in mean tumor volume for a compoundtreated group/the change in mean tumor volume of the control group(non-treated or vehicle treated)×100 (ΔT/ΔC) is subtracted from 100 togive the percent tumor growth inhibition (% TGI) for each test compound.In addition to tumor volumes, body weight of animals is monitored twiceweekly for up to 3 weeks. The results are shown in Table 3. In thetable, “A” indicates tumor growth inhibition of less than 25%; “B”indicates tumor growth inhibition of ≧25% but <50%; “C” indicates tumorgrowth inhibition of ≧50% but <75%; and “D” indicates tumor growthinhibition of ≧75%.

TABLE 3 In vivo efficacy of selected compounds dosed orally daily usingPEG 400/0.1 N HCl in saline (40/60) as a vehicle Du- ra- tion of Tumorex- Growth peri- Inhibi- Dosage Tumor ment tion Structure (mg/kg) type(days) (%)

20 MNNG HOS MKN45  6  7 A C

20 MKN45  7 B

20 MKN45  8 A

20 MKN45  8 B

20 MKN45  8 D

20 MKN45  8 B

20 U87MG 12 A

20 U87MG 10 B

20 SKLMS40 13 C

20 MKN45 14 A

20 U87MG 10 C

20 MKN45 A549 SKLMS40 13 12 13 C B A

40 20 MKN45 14 13 B B

20 MKN45 A549 U87MG SKLMS40 13 12 12 13 C C B A

20 MKN45 A549 U87MG SKLMS40 13 12 12 13 D C D C

20 MKN45 A549 13 12 B A

20 U87MG SKLMS40 MDAMB231 12 13 13 D D D

15 H1437 16 A

20 U87MG SKLMS Panc-1 13 15 13 D D D

20 HCT116 13 C

20 Panc-1 13 D

20 Panc-1 13 A

20 U87MG 13 D

20 SKLMS40 15 B

20 SKLMS40 15 D

20 SKLMS40 15 B

Assay Example 5 In Vivo Colloidal Neovascularization (CNV) Model

This test measures the capacity of compounds to inhibit CNV progression.CNV is the main cause of severe vision loss in patients suffering fromage-related macular degeneration (AMD).

Male Brown-Norway rats (Japan Clea Co., Ltd.) were used in thesestudies.

Rats were anesthetized by intraperitoneal injection of pentobarbital,and the right pupil was dilated with 0.5% tropicamide and 0.5%phenylephrine hydrochloride. The right eye received 6 laser burnsbetween retinal vessels using a slit lamp delivery system of Green laserPhotocoagulator (Nidex Inc., Japan), and microscope slide glass withHealon™ (AMO Inc) used as a contact lens. The laser power was 100 or 200mW for 0.1 second and spot diameter was 100 μm. At the time of laserburn, bubble production was observed, which is an indication of ruptureof Bruch's membrane which is important for CNV generation.

Rats were divided into the groups based on their body weight using SASsoftware (SAS institute Japan, R8.1) after laser irradiation (Day0).After animals were anesthetized, and the right pupil dilated (as abovementioned), the right eye of the animal received the compound or vehicleby intravitreal injection (5 or 10 μL/eye) at doses of 30 and/or 100nmol/eyeon Day1 and/or Day3 and/or Day7. The compounds were dissolved orsuspended in CBS, PBS, or other adequate vehicles before injection.

On Day 10, the animals were anesthetized with ether, and high molecularweight fluorescein isothiocyanate (FITC)-dextran (SIGMA, 2×10⁶ MW) wasinjected via a tail vein (20 mg/rat). About 30 min after FITC-dextraninjection, animals were euthanized by ether or carbon dioxide, and theeyes were removed and fixed with 10% formaline neutral buffer solution.After over 1 hour of fixation, RPE-choroid-sclera flat mounts wereobtained by removing cornea, lens and retina from the eyeballs. The flatmounts were mounted in 50% glycerol on a microscope slide, and theportion burned by laser was photographed using a fluorescence microscope(Nikon Corporation, excitation filter: 465-495 nm, absorption filter:515-555 nm). The CNV area was obtained by measurement ofhyper-fluorescence area observed on the photograph using Scion image.

The average CNV area of 6 burns was used as an individual value of CNVarea, and the average CNV area of compound treated group was comparedwith that of the vehicle-treated group. Results with some compounds ofthe present invention are shown in Table 4 and are indicated as % ofinhibition of CNV progression (“A” indicates greater than or equal to30% inhibition, and “B” indicates ≧10% to <30% inhibition).

TABLE 4 % Inhibition Cpd No. of CNV (Ex No.) Progression 13(49) A116(223) B  80(187) A 14(50) B 146(253) A 145(252) B 148(255) A 161(268)B 162(269) A 163(270) A 167(274) A 170(277) A 173(280) A 177(284) A

What is claimed is:
 1. A compound of Formula (I):

and pharmaceutically acceptable salts thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof, wherein, D is selectedfrom the group consisting of

M is

Z is selected from the group consisting of covalent bond, —O—; Ar isphenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl or C₁—C₄ alkoxy; andG is

each R³⁸ is independently selected from the group consisting of halo,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —C(O)NR³⁶R³⁹,—C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,—(CH₂)_(j)NR³⁹(CH₂)_(i)SO₀₋₂₎(CH₂)_(i)[O(CH₂)_(i)]_(j)(CH₂)_(j)R⁹⁹,—(CH₂)_(j)NR³⁹(CH₂)_(j)R¹⁰⁰ wherein each j is an integer independentlyranging from 0 to 4, n is an integer ranging from 0 to 6, x is aninteger ranging from 1-6, each i is an integer independently rangingfrom 1 to 3, and the —(CH₂)_(i)— and —(CH₂)_(n)— moieties of theforegoing R³⁸ groups are optionally substituted, and optionally includea carbon-carbon double or triple bond where n is an integer between 2and 6; R³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl,—O—C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),—(CH₂)_(n)(5-10 membered heterocyclyl) and —(CH₂)_(n)A⁴R³⁷, wherein eachn is an integer independently ranging from 0 to 6, A⁴ is selected fromthe group consisting of a covalent bond, O, S, SO, SO₂, and the alkyl,cycloalkyl, aryl and heterocyclyl moieties of the foregoing R³⁶ groupsare optionally substituted, with the proviso that when R³⁶ and R³⁹ areboth attached to the same nitrogen, then R³⁶ and R³⁹ are not both bondedto the nitrogen directly through an oxygen; each R³⁷ and R⁴¹ isindependently selected from H, —C₁-C₆ alkyl, —O—C₁-C₆ alkyl, —O—C₃-C₁₀cycloalkyl, —O—(CH₂)_(n)(C₆-C₁₀ aryl), —O—(CH₂)_(n)(5-10 memberedheterocyclyl), optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-C₁₀ cycloalkyl, optionally substituted—O—(CH₂)_(n)A⁴-C₁-C₆ alkyl, optionally substituted —O—(CH₂)_(n)A⁴-C₂-C₆alkenyl, optionally substituted —O—(CH₂)_(n)A⁴-C₂-C₆ alkynyl andoptionally substituted —O—(CH₂)_(n)A⁴-C₃-C₁₀cyclaoalkyl; R³⁹ is selectedfrom the group consisting of H, —OH, C₁-C₆ alkyl, —C(O)—C₁-C₆alkyl,—SO₂—C₁-C₆alkyl, —C(O)—O—C₁-C₆alkyl-aryl and a protecting group used toprotect secondary amino groups, with the proviso that when R³⁶ and R³⁹are both attached to the same nitrogen, then R³⁶ and R³⁹ are not bothbonded to the nitrogen directly through an oxygen; each R⁴⁰ isindependently selected from H, C₁-C₁₀ alkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10 membered heterocyclyl), wherein nis an integer ranging from 0 to 6; R⁹⁹ at each occurrence isindependently selected from the group consisting of —H, halogen,trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —S(O)₂NR³R³,—C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³,P(═O)(OH)₂, —P(═O)(C₁-C₆alkyl)₂, —SO₃H—C(O)R³, C₁-C₄ alkoxy, C₁-C₄alkylthio, —O(CH₂)₀₋₆aryl, —O(CH₂)₀₋₆heteroaryl, —(CH₂)₀₋₅(aryl),—(CH₂)₀₋₅(heteroaryl), -, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—CH₂(CH₂)₀₋₄-T², wherein the aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted; R¹⁰⁰ is a 12 to24-membered optionally substituted heteroalicyclic macrocycle containing4 to 8 oxygen atoms; each R³ is independently selected from the groupconsisting of —H and R⁴; R⁴ is selected from the group consisting of a(C₁-C₆)alkyl, an aryl, a lower arylalkyl, a heterocyclyl and a lowerheterocyclylalkyl, each of which is optionally substituted, or R³ andR⁴, taken together with a common nitrogen to which they are attached,form an optionally substituted five- to seven-membered heterocyclyl, theoptionally substituted five- to seven-membered heterocyclyl optionallycontaining at least one additional annular heteroatom selected from thegroup consisting of N, O, S and P; each R¹³ is independently selectedfrom the group consisting of —H, halogen, trihalomethyl, —CN, —NO₂,—NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, —C(O)SR³, C₁-C₄ alkoxy,C₁-C₄ alkylthio, —O(CH₂)₀₋₆aryl, —O(CH₂)₀₋₆heteroaryl, —(CH₂)₀₋₅(aryl),—(CH₂)₀₋₅(heteroaryl), —(CH₂)₀₋₅(cycloalkyl), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄alkylcarbonyl, and a saturated or unsaturated three- to seven-memberedcarboxyclic or heterocyclic group, wherein the aryl, heteroaryl, C₁-C₆alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted; twoR¹³, together with the atom or atoms to which they are attached, cancombine to form a heteroalicyclic optionally substituted with betweenone and four of R⁶⁰, wherein the heteroalicyclic can have up to fourannular heteroatoms, and the heteroalicyclic can have an aryl orheteroaryl fused thereto, in which case the aryl or heteroaryl isoptionally substituted with an additional one to four of R⁶⁰; R⁶⁰ isselected from the group consisting of —H, halogen, trihalomethyl, —CN,—NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, an optionallysubstituted (C₁-C₆)alkyl, an optionally substituted aryl, an optionallysubstituted heteroarylalkyl and an optionally substituted arylalkyl; ortwo R⁶⁰, when attached to a non-aromatic carbon, can be oxo; Q isC₁-C₆alkyl or a three- to ten-membered ring system, optionallysubstituted with between zero and four of R²⁰; each R²⁰ is independentlyselected from the group consisting of —H, halogen, trihalomethyl,—O-trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³, —OCF₃, —NR³R⁴, —S(O)₀₋₂R³,—S(O)₂NR³R³, —C(O)OR³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³,—N(R³)C(O)OR³, —C(O)R³, —C(O)SR³, C₁-C₄ alkoxy, C₁-C₄ alkylthio,—O(CH₂)₀₋₆aryl, —O(CH₂)₀₋₆heteroaryl, —(CH₂)₀₋₅(aryl),—(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄ alkylcarbonyl, C₁₋₄alkoxy, an amino optionally substituted by C₁₋₄ alkyl optionallysubstituted by C₁₋₄ alkoxy and a saturated or unsaturated three- toseven-membered carboxyclic or heterocyclic group and wherein the aryl,heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionallysubstituted; T² is selected from the group consisting of —OH, —OMe,—OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂; and X¹ is selected from thegroup consisting of O, S, CH₂, N—CN, N—O-alkyl, NH and N(C₁-C₆alkyl) X³and X⁴ are each independently selected from the group consisting of —H,halogen, cyano, nitro, C₁-C₆ alkyl, or X³ and X⁴ together with the atomto which they are attached form a C₃-C₄ cycloalkyl.
 2. The compoundaccording to claim 1, wherein each R³⁸ is independently selected fromthe group consisting of —C(O)O—(CH₂)_(n)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.
 3. The compound according to claim 1,wherein each R³⁸ is independently selected from the group consisting ofhalo, —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, and—(CH₂)_(j)NR³⁹(CH₂)_(j)R³⁶.
 4. The compound according to claim 1,wherein each R³⁸ is independently selected from the group consisting of—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂.
 5. The compound accordingto claim 4, wherein X¹ is O or S.
 6. The compound according to claim 1,wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein the —(CH₂)_(n)— groupis optionally substituted with C₁-C₆alkyl, R³⁶ is —(CH₂)_(n3)A⁴R³⁷,wherein each n3 is an integer independently ranging from 0 to 6, R³⁷ isoptionally substituted C₁-C₆ alkyl, and R³⁹ is —C(O)—C₁-C₃alkyl.
 7. Thecompound according to claim 1, wherein R³⁸ is independently selectedfrom the group consisting of halo, —C(O)O—(CH₂)_(n)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl), and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein each j is an integer independentlyselected from 0 to 4, n is an integer from 0 to 6, i is 2 or 3, R³⁹ is Hor C₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl),—(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, whereineach n3 is an independently selected integer ranging from 0 to 6, andR³⁷ is H or C₁-C₆alkyl.
 8. The compound according to claim 7, wherein Dis


9. The compound according to claim 1, wherein R³⁸ is independentlyselected from the group consisting of halo,—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR₁₃-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein X¹ is O or S, j isan integer from 0 to 4, n is an integer from 0 to 6, R³⁹ is H orC₁-C₆alkyl, and R³⁶ is selected from the group consisting of H, —OH,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl),—(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, wherein n3is an integer ranging from 0 to 6, and R³⁷ is H or C₁-C₆alkyl.
 10. Thecompound according to claim 9, wherein D is


11. The compound according to claim 1, wherein G is selected from thegroup consisting of

wherein each methylene in any of the above formulae, other than those ina depicted ring, is independently optionally substituted with R²⁵;R^(5a) is —H or an optionally substituted (C₁-C₆)alkyl; R¹⁰ is anazolyl, wherein one or more hydrogen atoms are optionally substituted bya moiety selected from the group consisting of a halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, trihalomethyl, nitro, amino optionallyindependently substituted by one or two of C₁₋₄ alkyl, a C₁₋₄alkoxycarbonyl C₁₋₄ alkyl, a C₁₋₄ alkylcarbonyl and a C₃₋₅ cyclic alkyl.12. The compound according to claim 1, wherein G is selected from thegroup consisting of


13. The compound according to claim 1, wherein G is selected from thegroup consisting of


14. The compound according to claim 1, wherein M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 15. The compound according to claim 1, wherein R³⁸ isindependently selected from the group consisting of halo,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),and —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein each j is an integerindependently selected from 0 to 4, n is an integer from 0 to 6, i is 2or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀aryl), —(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷,wherein n3 is an integer ranging from 0 to 6, and R³⁷ is H orC₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 16. The compound according to claim 1, wherein D is

M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 17. The compound according to claim 1, wherein D is

wherein R³⁸ is selected from the group consisting of halo,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)C₁-C₆ alkyl),and —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein each j is an integerindependently selected from 0 to 4, n is an integer from 0 to 6, i is 2or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀aryl), —(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷,wherein n3 is an integer ranging from 0 to 6, and R³⁷ is H orC₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 18. The compound according to claim 1, wherein M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein phenyl groups of G are optionally substituted with from 0 to 4independently selected R²⁰.
 19. The compound according to claim 1,wherein R³⁸ is independently selected from the group consisting of halo,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆alkyl),and —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein each j is an integerindependently selected from 0 to 4, n is an integer from 0 to 6, i is 2or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀aryl), —(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷,wherein n3 is an integer ranging from 0 to 6, and R³⁷ is H orC₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein phenyl groups of G are optionally substituted with from 0 to 4independently selected R²⁰.
 20. The compound according to claim 1,wherein D is

M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—alkyl orC₁—C₄ alkoxy; and G is

wherein phenyl groups of G are optionally substituted with from 0 to 4independently selected R²⁰.
 21. The compound according to claim 1,wherein D is

wherein R³⁸ is independently selected from the group consisting of halo,—C(O)O—(CH₂)_(n)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆alkyl),and —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein each j is an integerindependently selected from 0 to 4, n is an integer from 0 to 6, i is 2or 3, R³⁹ is H or C₁-C₆alkyl, and R³⁶ is selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀aryl), —(CH₂)_(n3)(5-10 membered heterocyclyl) and —(CH₂)_(n3)A⁴R³⁷,wherein n3 is an integer ranging from 0 to 6, and R³⁷ is H orC₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein phenyl groups of G are optionally substituted with from 0 to 4independently selected R²⁰.
 22. The compound according to claim 1,wherein R³⁸ is independently selected from the group consisting of halo,—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein j is an integerfrom 0 to 4, n is an integer from 0 to 6, R³⁹ is H or C₁-C₆alkyl, andR³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, wherein n3 is an integer rangingfrom 0 to 6, and R³⁷ is H or C₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 23. The compound according to claim 1, wherein D is

wherein R³⁸ is independently selected from the group consisting of halo,—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)(P═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein j is an integerfrom 0 to 4, n is an integer from 0 to 6, R³⁹ is H or C₁-C₆alkyl, andR³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, wherein n3 is an integer rangingfrom 0 to 6, and R³⁷ is H or C₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R^(20.)
 24. The compound according to claim 1, wherein R³⁸ isindependently selected from the group consisting of halo,—(CH₂)_(n)P(=O)(C₁—C₆alkyl )₂, —(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(=O)(C₁—C₆alkyl)_(2, —NR)¹³C(X¹)NR¹³—arylP(=O)(C₁—C_(6 alkyl)) ₂ and—NR¹³C(X¹)NR¹³—heteroarylP(=O)(C₁—C₆alkyl)₂, wherein j is an integerfrom 0 to 4, n is an integer from 0 to 6, R³⁹ is H or C₁—C₆alkyl, andR³⁶ is selected from the group consisting of H, —OH, C₁—C₆ alyl, C₃—C₁₀cycloalkyl, —(CH₂)_(n3)(C₆—C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, wherein n3 is an integer rangingfrom 0 to 6, and R³⁷ is H or C₁—C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogens, C₁—C₆ alkyl orC₁—C₄ alkoxy; and

wherein phenyl groups of G are optionally substituted with from 0 to 4independently selected R^(20.)
 25. The compound according to claim 1,wherein D is

wherein R³⁸ is independently selected from the group consisting of halo,—(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—(CH₂)_(j)NR³⁹CH₂(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂,—NR¹³C(X¹)NR¹³-arylP(═O)(C₁-C₆alkyl)₂ and—NR¹³C(X¹)NR¹³-heteroarylP(═O)(C₁-C₆alkyl)₂, wherein j is an integerfrom 0 to 4, n is an integer from 0 to 6, R³⁹ is H or C₁-C₆alkyl, andR³⁶ is selected from the group consisting of H, —OH, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n3)(C₆-C₁₀ aryl), —(CH₂)_(n3)(5-10 memberedheterocyclyl) and —(CH₂)_(n3)A⁴R³⁷, wherein n3 is an integer rangingfrom 0 to 6, and R³⁷ is H or C₁-C₆alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is,

wherein phenyl groups of G are optionally substituted with from 0 to 4independently selected R²⁰.
 26. The compound according to claim 1,wherein M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 27. The compound according to claim 1, wherein R³⁸ is—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from 0 to 4, n is aninteger from 0 to 6, and the —(CH₂)_(n)— group is optionally substitutedwith C₁-C₆alkyl, R³⁶ is —(CH₂)_(n3)A⁴R³⁷, wherein n3 is an integerranging from 0 to 6, wherein the R³⁷ is optionally substituted C₁-C₆alkyl, and R³⁹ is H or —C(O)—C₁-C₃alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 28. The compound according to claim 1, wherein, D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and the —(CH₂)_(n)— group isoptionally substituted with C₁-C₆alkyl, R³⁶ is —(CH₂)_(n3)A⁴R³⁷, whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H or —C(O)—C₁-C₃alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 29. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 30. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 31. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; G is

wherein R¹³ is H; and Q is optionally substituted with from 0 to 4independently selected R²⁰.
 32. The compound according to claim 1,wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; G is

wherein R¹³ is H; X³ and X⁴ are each H or taken together with the carbonto which they are attach are cyclopropyl; and Q is cycloalkyl,heteroaryl or phenyl, optionally substituted with from 0 to 4independently selected R²⁰.
 33. The compound according to claim 1,wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; G is

wherein R¹³ is H; X³ and X⁴ are each H or taken together with the carbonto which they are attach are cyclopropyl; and Q is cyclopropyl,isoxazole or phenyl, optionally substituted with from 0 to 2independently selected halogen, C₁-C₆alkyl or —CF₃.
 34. The compoundaccording to claim 1, wherein, D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen, C₁—C₆ alkyl orC₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 35. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 36. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; G is

wherein R¹³ is H; and Q is optionally substituted with from 0 to 4independently selected R²⁰.
 37. The compound according to claim 1,wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; G is

wherein R¹³ is H; X³ and X⁴ are each H or taken together with the carbonto which they are attach are cyclopropyl; and Q is cycloalkyl,heteroaryl or phenyl, optionally substituted with from 0 to 4independently selected R²⁰.
 38. The compound according to claim 1,wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen, C₁—C₆alkyl or C₁—C₄ alkoxy; G is

wherein R¹³ is H or C₁-C₆ alkyl; X³ and X⁴ are each H or taken togetherwith the carbon to which they are attach are cyclopropyl; and Q iscyclopropyl, cyclopentyl, cyclohexyl, pyridine or phenyl, optionallysubstituted with from 0 to 2 independently selected halogen, C₁-C₆alkyl,—S(O)₂(C₁-C₆)alkyl, —C(O)NH₂, —C(O)(C₁-C₆)alkyl or —CF₃.
 39. Acomposistion comprising a compound according to claim 1 and apharamaceutically acceptable carrier.
 40. The compound according toclaim 1, wherein, D is

wherein R³⁸ is C₁-C₆alkyl or —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is aninteger from 0 to 4, n is an integer from 0 to 6, and the —(CH₂)_(n)—group is optionally substituted with C₁-C₆alkyl, R³⁶ is—(CH₂)_(n3)A⁴R³⁷, wherein n3 is an integer ranging from 0 to 6, whereinthe R³⁷ is optionally substituted C₁-C₆ alkyl, and R³⁹ is H or—C(O)—C₁-C₃alkyl; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 41. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with 0 to 4 halogen; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 42. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen; and G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.
 43. The compound according to claim 1, wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen; G is

wherein R¹³ is H; and Q is optionally substituted with from 0 to 4independently selected R²⁰.
 44. The compound according to claim 1,wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen; G is

wherein R¹³ is H; X³ and X⁴ are each H or taken together with the carbonto which they are attach are cyclopropyl; and Q is cycloalkyl,heteroaryl or phenyl, optionally substituted with from 0 to 4independently selected R²⁰.
 45. The compound according to claim 1,wherein D is

wherein R³⁸ is —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is an integer from0 to 4, n is an integer from 0 to 6, and R³⁶ is —(CH₂)_(n3)OR³⁷ whereinn3 is an integer ranging from 0 to 6, wherein the R³⁷ is optionallysubstituted C₁-C₆ alkyl, and R³⁹ is H; M is

Z is —O—; Ar is phenyl substituted with at least one halogen; G is

wherein R¹³ is H; X³ and X⁴ are each H or taken together with the carbonto which they are attach are cyclopropyl; and Q is cyclopropyl,isoxazole or phenyl, optionally substituted with from 0 to 2independently selected halogen, C₁-C₆alkyl or —CF₃.
 46. The compoundaccording to claim 1, wherein the compound has the structure:


47. The compound according to claim 46, wherein the compound has thestructure:


48. The compound according to claim 46, wherein the compound has thestructure:


49. The compound according to claim 46, wherein the compound has thestructure: